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I

I Blood Group (Ii system): I and i are universal


erythrocyte antigens that exhibit alteration during
development but minimal polymorphism. The syn-
thesis of I/i antigens results from the cooperation of
glycosyltransferases on common substrates and there
is not a single diagnostic immunodeterminant sugar
specific for the blood type. It may be associated with
autoimmune hemolytic anemias. blood types,
ABO blood type, hemolytic disease, hemolytic
anemia
I Element: non-viral retrotransposable elements,
retroposon, retrotransposon
I.U: International unit is a quantity of various vitamins,
hormones, enzymes, etc. that bring about a standard
response as determined by the International Confer-
ence for Unification of Formulas.
IAA: Denotes indole acetic acid. plant hormones. (see
Fig. I1).
H
N
CH
2
COOH
Figure I1. Indole-3-acetic acid
IAM: infinite allele mutation model, microsatellite,
minisatellite, SMM model
IAP: chloroplast import
IAP (intracisternal [within closed compartments] A
particles): These are retroviral elements in the mouse
genome capable of transposition. They are normally
not active but demethylation of their long terminal
repeats increases their transcription 50100 fold.
Male germ cells are demethylated shortly before the
formation of the spermatogonia. Female germs are
demethylated slightly later but only during the period
between the primordial germ cells and growing
oocytes. The spermatogonia and the oocytes are
heavily methylated. The IAP elements are not found
in humans. Prader-Willi syndrome, dyskeratosis;
Vogler C et al 2001 Pediatr Res 49(3):342.
IAP (inhibitor of apoptosis): Controls apoptosis by
binding or in other ways interfering with caspase or
pro-caspase activation. At its N-terminus it contains
one or more BIR motifs and its C-terminus has a
RING finger domain for recruiting caspase. The
IAPs are involved in ubiquitin ligase activity and may
autoregulate their degradation by proteasomes. The
expression of a construct containing the RING
domain of X-linked IAP causes its ubiquitylation
and degradation by the proteasome. This results in
apoptosis and markedly reduced melanoma prolifer-
ation following the administration of cisplatin (Silke J
et al 2005 Proc Natl Acad Sci USA 102:16182). The
Smac/DIABLOprotein binds to the IAPand promotes
caspase activity. Binding proteins REAPER, HID
and/or GRIM promote caspase activity presumably
by neutralizing the IAP. apoptosis, BIR, cas-
pase, RING finger, ubiquitin, proteasome,
Smac, DIABLO, melanoma, cisplatin;
Verhagen AM et al 2001 Genome Biol 2: reviews
3009; Sharief MK, Semra YK 2001 J Neuroimmunol
119:350.
IARC: The International Agency for Research on
Cancer, Lyon, France, publishes reviews on carcino-
gens as scientific publications of the IARC. cancer,
environmental mutagens, databases; http://www.
iarc.fr/.
Iatrogenic: (adjective) Refers to the adverse effect(s)
resulting from or concomitant to medical treatment,
hospital-acquired infections. nosocomial
IBD: Identical by descent refers to an allele inherited
from an ancestor that is exactly the same as that of the
particular ancestor and not the result of a new
mutation identical by state (IBS). IBD-APM means
identical by descent for affected-pedigree-member.
More information can be obtained by combining
conventional linkage tests with high-resolution single
nucleotide polymorphism scans (Burdick JT et al
2006 Nature Genet 38:1002). inbreeding coeffi-
cient, SNIP
ibid: An abbreviated form of the Latin adverb ibidem
means the same place; it is sometimes used in
citations when another paper appears at the same
place, i.e., in the same journal.
IBIDS: ichthyosis
IbpA, IbpB (Inclusion Body Proteins): These are small
heatshock protein chaperones of prokaryotes.
sHSP; Kitagawa M et al 2000 FEMS Microbiol
Lett 184(2):165.
IBS: IBD, identity of state
IC
50
: Refers to median inhibitory concentration
(of a drug or other chemical compound).
ICAD (inhibitor of CAD): CAD, caspase, AIF;
Sakahira H et al 1999 J Biol Chem 274:15740.
ICAM (CD54, intercellular adhesion molecule,
19p13.3-p13.2): These proteins bind together
ICAM 951
I
(epithelial) cells through integrins. The concentration
of ICAM-2 in uropod projections, rather than being
evenly distributed, is a special target for cytotoxic
lymphocytes (CTL). The targeting is assisted by the
cytoskeletal - membrane linker protein ezrin. ICAM-
1 protects against allograft rejection. N-CAM,
cadherin, integrin, DC-SIGN, CD proteins,
dengue fever, LFA, uropod, T cell; Springer
TA 1990 Nature [Lond] 346:425; Sultan P et al 1997
Nature Biotechnol 15:759; crystal structure: Song G
et al 2005 Proc Natl Acad Sci USA 102:3366.
ICAT (isotope-coded affinity tag): This is a protein
analytical procedure that may be substituted for the
two-dimensional gel electrophoresis. The cells are
grown under two different conditions and a biotin-
linked isotope is used to label the cysteine residues of
the proteins. The extracted protein is digested and
the labeled peptides are subjected to affinity chroma-
tography and the peptides are further analyzed by
high-performance liquid chromatography/mass spec-
trometry. Differences in the expression of genes are
demonstrated by differences at the level of the
isotope. gel electrophoresis, two-dimensional
gel electrophoresis, MALDI/TOF/MS, proteo-
mics; Smolka MB et al 2001 Anal Biochem 297:25;
Han DK et al 2001 Nature Biotechnol 19:946;
Turecek F 2002 J Mass Spectrom 37:1.
Iccosomes: Dendritic cells package antigen: antibody
complexes into budding structures that shed from
their surface. dendritic cell; Terashima K et al 1992
Semin Immunol 4(4):267.
ICE (interleukin-1 converting enzyme, caspase 1 in
human chromosome 11q22): A cysteine protease
which is activated during Fas-mediated apoptosis.
Its family includes CPP32 and Ich-1 proteases. The
ICE is a mammalian homolog of ced-3. Fas,
apoptosis, interleukins, CPP32, granzyme
B, RNKP-1, IL-1, caspase; Druilhe A et al
2001 Cell Death Differ 8(6):649.
Ice Man (tzi): A frozen mummy was discovered in
1991 in the Tyrolean Alps, its age was estimated to be
5,100 to 5,300 years. Some claims have been made
that it may be a scientific hoax but detailed analysis
has negated this possibility. Also, 10-genome equiv-
alent quantity of DNA per gram of its tissue,
comprising only redundant sequences, has been
recovered. One DNA sequence of the hypervariable
region of the mitochondrial DNA indicated close
similarities to central and north European popula-
tions. The cause of his death as revealed by an X-ray
was an arrow flint. DNA analysis revealed four
different types of blood on his clothing leading to the
conclusion that he was involved in bloody fighting
with others. mtDNA, ancient DNA, mummies;
Williams AC et al 1995 Biochim Biophys Acta
1246:98; Bortenschlager S, Oeggl K eds. 2000 The
Iceman and His Natural Environment. Springer,
Wien, Austria.
Iceland: The Icelandic population has been consid-
ered one of the genetically most homogeneous
populations in the world in terms of blood group,
allozyme data and mitochondrial DNA (Helgason A
et al 2000 Am J Hum Genet 66:999). However, a re-
examination of the mitochondrial DNA diversity
does not confirm the validity of this view (rnason E
2003 Ann HumGenet. 67:5). The latter viewhas been
questioned, as it is thought to be based on inappropri-
ate comparisons (Helgason A, Stefnsson K2003 Am
J Hum Genet 73:947).
I-Cell Disease: mucopolysaccharidosis
ICER (inhibitor of CRE): A basic leucine zipper domain
protein of the CREB family lacking the C-terminal
transactivation domain. It is inducible by FSH.
CRE, CREB, FSH, leucine zipper; Trocme
C et al 2001 J Neurosci Res 65(2):91.
ICF: immunodeficiency, methylation of DNA
ICH1: This is a protease implicated in apoptosis. Its
N-terminus is homologous to caspase 2. apoptosis,
caspase; Zeng Q et al 2000 J Comp Neurol 2000
424:640.
Ichthyosis: This non-inflammatory keratosis of the skin
appearing in different forms under different genetic
controls is often associated with various syndromes
(see Fig. I2). In the autosomal dominant (with poor
penetrance) ichthyosis vulgaris (1q21), the scaling of
palms and soles appears during the first three months
after birth and it may be caused by keratohyalin
deficiency, a precursor of filaggrin, an element of
keratin fibers (Smith FJD et al 2006 Nature Rev
Genet 38:337). Sequencing of this large, highly
repetitive gene has revealed 15 variants, including
seven that are prevalent. All the variants are either
nonsense or frameshift mutations that, in representa-
tive cases, result in loss of filaggrin production in
the epidermis and manifest childhood eczema
(Sandilands A et al 2007 Nature Genet 39:650).
There are a number of variations of the dominant
types. Its incidence among schoolchildren in England
was 1/250. The autosomal recessive lamellar
(14q11.2, keratinocyte transglutaminase, TGM1)
form has many variations involving redness of the
skin, brittle hair, blisters, liver disease, physical and
mental retardation, etc. There are other recessive
lamellar ichthyosis genes in human chromosome
2 (LI2, 2q33-35) and LI3 is located at 19p12-q12. The
recessive forms are generally more serious than the
dominant ones. The harlequin type (2q34; so named
952 ICAT
I
because the diamond-shaped 45 cm diameter scaly,
horny spots resemble the diamond-patterned costume
of a harlequin) may cause death within the first week
after birth. The defect is in the ABC transporter A12.
Some recessive forms involve hair loss, progressive
neural defects, enlarged liver and kidney defects. In
the Sjgren-Larsson syndrome (17p11.2) the fre-
quency of the recessive gene responsible for the
disease in a county of Sweden was 0.01 and that of
carriers was 0.02 while the prevalence was 8.3 10
5
.
Fatty aldehyde dehydrogenase deficiency, neuro-
logical disorders and keratosis characterize this
latter form of ichthyosis. Another form of recessive
ichthyosis is related to triglyceride storage anomalies.
In the autosomal recessive ichthyosis (14q11) the
activity of keratinocyte transglutamase activity is
considerably reduced. X-linked ichthyosis (Xp22.32)
based steroid sulfatase deficiency may produce
asymmetric malformations of the lung, thyroid,
several nerves, etc. and hypoplasia on the same side
as the ichthyosis. Another X-linked (distal part of Xp)
group reveals deficiency of placental steroid sulfa-
tase. This is also called IBIDS. keratosis, skin
disease, collagen, lyonization, trichothiody-
strophy, collodion fetus, filaggrin, Chanarin-
Dorfman disease, erythroderma, eczema
Figure I2. Ichthyosis
ICOS (inducible co-stimulator, a human homolog of
CD28): This is a homodimeric protein (M
r
5560K)
which enhances T cell proliferation, lymphokine
secretion, upregulates cell-to-cell interaction, anti-
body production by B cells and the production of
IL-10 (but not IL-2) in response to foreign antigens.
The B7 related protein (B7RP) expressed on B cells
and ICOS without interacting with the B7CD28
system, stimulates adaptive immune response.
ICOS
/
mice are deficient in immunoglobulin class
switching and germinal center formation. CD40 and
its ligand may compensate for the ICOS defects. The
ICOS may influence T
H
-1 and T
H
-2 lymphocytes
and may be partly responsible for graft rejection
and autoimmune disease. CD28, B7 protein,
CTLA, IL-10, IL-2, T cell receptor, immu-
noglobulin, germinal center, CD40, autoim-
mune disease; McAdam AJ et al 2001 Nature
409:102; zkaynak E et al 2001 Nature Immunol
2:591 and following articles.
Icosahedral: This is a body with 20 facets like the
capsids of some viruses. isometric phage
ICR: Compounds synthesized by the International
Cancer Research Institute, Philadelphia, are acridines
with alkylating side chains and cause frameshift
mutations. mutagens
ICR: Refers to the internal control regions through the
zona pellucida. A box
ICR (insulator control region): enhancer competition,
insulator
ICSI (intracytoplasmic sperm injection): Spermatozoa
in some humans and animals are unable to penetrate
the egg. In such cases the spermatozoon may be
injected mechanically into the ooplasm. This tech-
nology can also be used for genetic transformation.
However, there are some risks of mechanical or
chemical (in the delivery fluid) injury to the egg. The
genetic risk is that the spermatozoon injected is not
competing and a less viable or defective one may
fertilize. This method enables men with a very low
sperm count to father children. Unfortunately, the
genetically determined low sperm count is transmit-
ted to the offspring. Mouse and human spermatozoa
have small acrosomes compared to bulls, boars and
hamster and the inclusion of the acrosome during
ICSI can be very harmful to the oocytes in as much as
lysis and deformation can occur (Morozumi K,
Yanagimachi R 2005 Proc Natl Acad Sci USA
102:14209). The removal of both the plasma
membrane and acrosome from the mouse spermato-
zoa before the ICSI not only accelerates the onset of
oocyte activation, but also results in improved
embryonic development (Morozumi K et al 2006
Proc Natl Acad Sci USA 103:17661). ART,
in vitro fertilization, acrosome; Ma S et al 2001
Fertility & Sterility 75:1095; Faddy MJ et al 2001
Nature Genet 29:131; Cox GF et al 2002 Am J Hum
Genet 71:162.
Icterus: A technical term for jaundice. kernicterus,
hyperbilirubinemia
ID: idant
ID (integrating database): This is formed in the
GenBank containing information on accession num-
ber, ASN.1, gi, Bioseq. GenBank, accession
number, ASN.1, gi, Bioseq
ID
50
: Refers to the dose of an infectious agent that
infects 50% of the cells exposed to it.
ID Proteins: These interfere with differentiation by
blocking the access of basic helix-loop-helix tran-
scriptions factors to the E box in the DNA. In mice
there are four Id genes and knocking out all of them is
ID Proteins 953
I
lethal, but when at least one allele is functional
premature withdrawal of the neuroblasts from the cell
cycle and failure of the normal angiogenesis and
vascularization occur. Overexpression of Id2 is due to
the activation of the transcription of the Myc family
of oncoproteins. For the progression of the cell cycle
induced by Myc requires the inactivation of Rb
(retinoblastoma) protein by the dominant-negative
Id2. Id1 opposes the effect of p16
INK4q
in senescence.
The degradation of Id2 by the anaphase-promoting
complex (APC-CDH1) and D box motifs promotes
axonal growth (Lasorella A et al 2006 Nature [Lond]
442:471). E box, D box, anaphase promoting
complex, Cdh1, angiogenesis, helix-loop-he-
lix, retinoblastoma, Myc, p16
INK4a
, senes-
cence; Alani RM et al 2001 Proc Natl Acad Sci USA
98:7812.
Idant: A higher hierarchical genetic structure as
conceived during the early/middle nineteenth centu-
ry. Biophores (alleles) aggregated into ids (loci)
and ids formed idants (chromosomes).
Idaxozan: clonidine
IDC (Idiopathic Dilated Cardiomyopathy): cardiomy-
opathy dilated
IDDM: Denotes insulin-dependent diabetes mellitus.
diabetes mellitus
Identical By Descent: IBD
Identical By State: IBD
Identical Twins: twinning
Identifier: Sequences within introns or non-coding 3
regions are involved in genetic regulation. The
identifier sequences are transcribed by RNA poly-
merase III and may define chromatin regions and
facilitate the transcription by RNA polymerase II as
promoters are made more accessible to soluble
transacting molecules. introns, regulation of gene
activity, RNA polymerase, transacting element;
Mellon SH et al 1988 Nucleic Acids Res 16:3963.
Identifier Syntax: In the BLAST search program this
indicates the source of the information, e.g., Gen-
Bank, EMBL and Swiss-Prot. gi
Identity By Descent (IBD): The shared gene(s) in a
pedigree is derived from a common ancestor and is
not due to an identical mutation (identity by state).
Identity Gene: This controls developmental specifica-
tions for an organ. (Science 2002 296:297316)
Identity Index: evolutionary distance
Identity of State: When the coefficient of inbreeding is
determined, the identity of an allele must be specified
as identity by descent (i.e., passed on by a common
ancestor) not by coincidentally occurring mutation.
Mutation may generate only identity by state.coef-
ficient of inbreeding, consanguinity
Idiogram: This is a diagram of the chromosome set,
including all essential morphological features of chro-
mosomes, such as arm ratio, satellites and banding
pattern (see Fig. I3).
1
1
1
1
1
1
1
1
3
3
3
3
2
2
3
2
2
2
2
2
2
1
Figure I3. Idiogram
Idiomorphs: Refer to the opposite mating type-
determining gene loci in fungi. Typically, they
occupy the same location in various haplotypes but
have a different sequence (Arie Tet al 2000 Mol Plant
Microbe Interact 13:1330).
Idiopathic: This means spontaneous, i.e., the cause or
origin is unknown.
Idiopathic Hypogonadotropic Hypogonadism: hypo-
gonadotropic hypogonadism
Idiopathic Torsion Dystonia (ITD, DYT1, Torsin A):
This is a dominant (human chromosome 9q34)
neurological disorder (30% penetrance) with onset
before the late 20s, it first affects the limb muscles
and the effects may later spread. Its incidence (1.65
10
4
) is higher among Ashkenazy Jews compared to
other populations. Torsin A is a protein of the ATPase
family. dystonia; Clarimon J et al 2005 Ann Neurol
57:765.
Idiopathic Ventricular Fibrillation (IVF): This is a
common cause of fatal heart disease involving
arrhythmia. Missense or splice-donor mutations in
cardiac sodium channel gene SCN5A may increase
the risk of developing this condition.
Idioplasm: A nineteenth century hypothetical concept
about the physical basis of heredity.
Idiotope: Refers to the determinant of antigenic
specificity. antigen, antibody
Idiotype: The term was originally coined in 1884 for
identifying the entire complex of genetic determi-
nants in a cell but it is no longer used in that sense. In
modern immunogenetics it refers to idiotopes that
distinguish one group of antibody producing cells
954 Idant
I
from other groups of immunoglobulin producing
cells. Thus, the idiotype represents the specificity of
all the idiotopes because the antigens bind within or at
the idiotopes to the variable region of the antibody.
The recurrent (also called public, major or cross-
reactive) idiotypes regularly appear during the
immune response but the private (or minor) idiotypes
may or may not appear even in genetically identical
individuals. epitope, paratope, allotype, iso-
type, antibody, immunoglobulins, HLA, anti-
idiotype, internal image immunoglobulin; Jerne
NK 1985 Science 229:1057.
Idiotype Exclusion: In a family of genes only one gene
product is expressed. allelic exclusion, locus
exclusion
Idling Reaction: In amino acid starved cells synthetic
activity is reduced stringent control., and the
ribosomes are uncharged with aminoacylated tRNAs.
Under such conditions uncharged tRNAs may be
attached to the ribosomes and block any residual
protein synthetic activity as the idling reaction.
protein synthesis; Bilgin N et al 1992 J Mol Biol
224:1911.
iDNA (initiator DNA): At the onset of DNA replication
the polymerase /primase synthesizes it before
polymerase takes over the chain elongation.
replication fork, DNA replication; Law A et al
1998 Nucleic Acids Res 26:919.
Iduronic Acid: This is an epimer (a diastereomer
[stereoisomers without being mirror images]) of
glucuronic acid and dermatan sulfate, heparan sulfate
and heparin. mucopolysaccharidosis, Hurlers
syndrome, glucuronic acid, heparin
IES: internally eliminated sequences
IEX (immediate early expressed protein): This may
block apoptosis induced by FAS and TNF. Its
function is mediated by NF-B. apoptosis, NF-
B, TNF, FAS; Segev DL et al 2001 J Biol Chem
276:26799.
IF-1, IF-2, IF-3: These are protein synthesis initiation
factors in prokaryotes and eukaryotic organelles. IF-1
is a ribosome dissociation factor and it cooperates
with IF-2 and IF-3. IF2-1 and IF2-2 facilitate the
binding of the tRNA
fMet
to the AUG translation
initiation codon on the 30S ribosomal subunit. In
E. coli IF2-1 is a 97.3-kDa single polypeptide with
a GTP binding domain in its center. IF2-2 is 79.7
kDa? IF-3 (20.7 kDa) is a ribosome subunit anti-
association factor and a facilitator of tRNA
fMet
and
initiator codon interaction. In the eukaryote Saccha-
romyces there is a (FUN1 gene product yIF2)
homolog to the IF2. The eukaryotic eIF2 is a three
subunit functionally similar but structurally different
protein. The yIF2 is present in an evolutionarily
similar form from Archaebacteria to eukaryotes.
protein synthesis, eIF, alarmone, Shine-
Dalgarno sequence; Carter AP et al 2001 Science
291:498.
IFGT (irradiation and fusion gene transfer): Human
chromosomes are fragmented by irradiation (3
Krad) and then allowed to hybridize somatically with
rodent chromosomes. From such a cell culture the
majority of human chromosomes and fragments are
eliminated but those fragments that recombine with
the chromosome are retained. The co-retention of
human markers sheds light on their physical
proximity within the human chromosomes. somatic
cell hybrids, chromosome assignment, radiation
hybrid; Walter MA, Goodfellow PN 1995 Mol
Biotechnol 3(2):117.
IFN: interferons, IFR
IFN-Gamma: This is the same as MAF, a lymphokine.
IFR (interferon regulatory factor): This is a negative
regulator of interferon and when it binds to CCE it
activates histone 4 transcription, involved in the
progression from the G1 to the S phase of the cell
cycle. histones, interferons, HiNF, CCE,
cell cycle; Nakaya T et al 2001 Biochem Biophys
Res Commun 283:1150.
Ig: This means immunoglobulin (with additional letters
to identify various types). antibody, immunoglo-
bulins, immune system
Ig and Igb: These are immunoglobulin-associated
proteins that form disulfide linked heterodimers
(IgIg). They belong to a large family of antigen
receptor-associated signal transducers and include a
tyrosine-containing cytoplasmic motif. B cell activa-
tion requires this dimer for triggering the Src and Sky
family kinases for receptor phosphorylation. These
proteins play an additional regulatory role. The
heterodimer is essential for the differentiation of B
cells. lymphocytes, immunoglobulins, Src,
Sky, CD40; Rudolph AK et al 1981 Eur J
Immunol 11(6):527.
IGCs: speckles intranuclear
IGF: insulin-like growth factor
IGI (integrated gene index): This is a list of all genes
revealed in a genome. IPI
IGM (inheritable genetic modification [of humans]):
GMO
IgNAR: This is an atypical immunoglobulin heavy chain
(in cartilaginous fishes) which does not associate with
IgNAR 955
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a light chain. Each heavy chain has one variable and
five constant domains. immunoglobulins, anti-
body; Stanfield RL et al 2004 Science 305:1770.
Ignorant DNA: This molecular by-product of coinciden-
tal amplification may be slightly harmful but may
also be beneficial under certain circumstances, e.g.,
rRNA and satellite sequences. selfish DNA, junk
DNA, satellite; Epplen JT 1988 J Hered 79(6):409.
IGS: intergenic spacer
IgSF (immunoglobulin superfamily): The cell adhesion
molecules (CAM) commonly contain immunoglobu-
lin domains. These domains have a core with two
face-to-face arranged -sheets and highly variable
other regions. immunoglobulins, CAM, protein
structure
IGTC: International Gene Trap Consortium: http://www.
genetrap.org/; trapping promoters
I
h
(I
f
): Refers to hyperpolarization-activated cation
channels (HAC) in the cell membrane activated by
cAMP and cGMP controlled Na
+
/K
+
ion. Such a
process determines the pacemaker activity of active
neurons and heart cells. The three cloned HACs
contain 863, 910 and 779 amino acids, respectively.
hyperpolarization, ion channels
IHF (integration host factor): A heterodimeric host
protein that is required for site-specific recombina-
tion. It may also have some function in transcription
and replication. It is a member of the high mobility
group proteins and its function may bear some
similarity to that of histones in eukaryotes. high
mobility group proteins, site-specific recombina-
tion, recombination, intasome; Holbrook JA et al
2001 J Mol Biol 310:379.
iHOP (information hyperlinked over proteins): This
contains 12 million sentences over 80,000 genes for
more than 1,500 organisms, including humans, mice,
Drosophila, Caenorhabditis, zebrafish, Arabidopsis
yeast, E. coli and others. http://www.pdg.cnb.uam.es/
UniPub/iHOP
Ii Genes: ABO blood group
Ii: This is an invariant chain of the major histocompati-
bility complex involved in the assembly of class II
molecules in the endoplasmic reticulum. This chain is
subsequently degraded by lysosomal proteinases and
amino acids 81104 are retained as CLIP (class II-
associated Ii peptide) before the foreign antigen is
loaded on to the T lymphocytes and it is removed by
chaperone H-2M. major histocompatibility com-
plex, HLA; Frauwirth K, Shastri N 2001 Cell
Imunol 209(2):97.
iIF-3P: Refers to the translation elongation factor
stimulating the preinitiation complex on the 40S
ribosomal subunit. protein synthesis, eIF, PIC
IIH: This is shorthand for TFIIH. transcription factors
I
KAch
: Inwardly rectifying acetylcholine regulated K
+
channel, activated by G
i
protein, inhibits the opening
of the voltage-gated Ca
2+
channels and thus regulates
nerve and muscle functions. ion channels, G
i
protein
Ikaros: A transcriptional regulator of lymphocytes
which is associated with pericentromeric heterochro-
matin. The gene is alternately spliced to generate
multiple zinc finger proteins involved in gene
regulation and chromatin remodeling. heterochro-
matin, lymphocytes; Trinh LA 2001 Genes Dev
15:1817; Lopez R A et al 2002 Proc Natl Acad Sci
USA 99:602.
IkB (inhibitor of NF-B): This regulatory protein
binding to transcription factor NF-B retains it in
the cytoplasm until it is degraded by proteolysis after
being phosphorylated, and then it releases the
transcriptional activator NF-B to migrate into the
nucleus. The inactivation of IB usually requires
stress signals or a pathogenic attack. Ankyrin repeats
characterize the various types of IB and are also
present in several morphogenetic factors of Drosoph-
ila (e.g., cactus). The Epstein-Barr virus nuclear
antigen contains glycine-alanine (GA) repeats, which
are inhibitory to cis MHC class I restricted antigen
presentation. Thus, it prevents the activation of
cytotoxic T cells (CTL) and the virus may evade
immune recognition. The insertion of GArepeats into
the IB chain protects it from ubiquitination and
thereby the activation of the NF-B transcription
factor (see Fig. I4). Phosphorylation and proteolytic
cleavage are key instruments in the separation of IB
from the NF-B complex and it gives the two NF-B
subunits a chance to migrate into the nucleus and
serve as transcription factors. The phosphorylation of
IB is carried out by the morphogenesis factor and
cytokine-activated kinases IKK- and isozymes
(M
r
7090 K), respectively. IKK is part of a large
complex which also includes an associated scaffold
protein (IKAP, 150 K M
r
). IB is modified by the
ubiquitin-carrier protein SUMO-1 and it is therefore
not ubiquitinated and protected from degradation by
proteasomes. While ubiquitination is favored by
phosphorylation, SUMO-1 is inhibited by phosphor-
ylation. IB is an inducible protein which regulates
the expression of the Toll/IL-1 receptor and asso-
ciated genes (Yamamoto M et al 2004 Nature [Lond]
430:218).
IB-Ras1 and 2 proteins degrade the IB
subunit at a lower rate than the subunit.
956 Ignorant DNA
I
signal transduction, regulation of gene activity,
NF-B, FADD, RIP, TRADD, MAPKKK,
PEST, TNF, glucocorticoid, immunosuppres-
sion, ankyrin, morphogenesis in Drosophila,
ubiquitin, antigen presenting cell, PIC, IKK,
NIK, RAS; Imbert Vet al 1996 Cell 86:787; Pahl
HL 1999 Oncogene 18:6853; Bottero Vet al 2001 J
Biol Chem 276:21317; Ruefli-Basse AA et al 2003
Science 302:1581.
IKK: Denotes IB protein serine kinases. IKK (IKK1)
responds to morphogenetic signals in the activation of
NF-B whereas IKK responds to proinflammatory
cytokines and controls NF-B, which in turn
regulates inflammation and apoptosis. IKK phos-
phorylates histone H3 and thus mediates cytokine-
induced gene expression of NF-B-dependent genes
(Yamamoto Y et al 2003 Nature [Lond] 423:655).
IKK (NEMO) is a modulatory subunit of NF-B.
Aspirin inhibits IKK. IB, NAK, NF-B,
NEMO, aspirin, cyclooxygenase, Akt, ec-
todermal dysplasia, prostate cancer; Senftleben U
et al 2001 Science 293:1495.
IL: Refers to interleukin. (See ONeill LAJ, Bowie A
eds. 2001 Interleukin Protocols, Humana Press,
Totowa, NJ, USA).
IL-1: This is a lymphocyte-activating factor. The IL-1
(17-kDa) and (also about 17-kDa) chains are
encoded in human chromosome 2q13 at very close
linkage. IL-1ra is a cytokine receptor antagonist of
IL-1. The IL-1 receptors (IL-1R) are encoded close by
in human chromosome 2. IL-1 mediates Se/Thr
phosphorylation of various proteins (cytoskeleton)
and Hsp27. The Il-1 activated Ser/Thr kinase is IRAK
and the specific transduced molecule is TRAF6.
These molecules are elements of the NF-B cascade.
The IL-1 system is involved with the hematopoietic
cells, the neuroendocrine and the central nervous
systems. It generally cooperates with TNF. IL-1 has
clinical implications for inflammations, blood coagu-
lation, osteoporosis, metastasis, neurodegenerative
and autoimmune diseases. interleukins, IL-17,
prostaglandin, Toll, mental retardation, den-
dritic cell, ICE, NF-B, IRAK, TNF,
hepcidin; Bomford R, Henderson B eds. 1990
Interleukin-1, Elsevier, New York.
IL-2: Refers to the T-cell growth factor, TCGF, a 15.5-
kDa glycoprotein, encoded at 4q26-q27. It promotes
the proliferation and differentiation of lymphocytes.
The discovery of IL-2 has made possible the long
time culture of T cells. The IL-2R and the IL-2R
chain subunits are members of the cytokine receptor
superfamily. The IL-2R (human chromosome
22q11.2-12) and (Xq13) chains are shared by the
other IL receptors. The human IL2R (chromosome
10p14-p15) has only 13 amino acids in its cytoplas-
mic domain and it may not have a significant role in
signal transduction. The IL-R receptor complex has a
prominent role in various signal transduction path-
ways. Mice with the IL-2 receptor chain (IL-R)
show excessive differentiation of B cells into plasma
cells and excessive amounts of immunoglobulins G1
and E and the production of autoantibodies resulting
in hemolytic anemia. Defects in the widely shared IL-
2R cause severe combined immunodeficiency
(SCID) in humans. It is synthesized primarily by
CD4
+
-T
H
lymphocytes. The IL-2 gene is activated by
a Jun kinase at the 5-untranslated region and also
modulated at the 3-untranslated sequences. IL-2 may
serve as an adjuvant in genetic immunization.
interleukins, B cells, T cells, immunoglobu-
lins, autoantibody, anemia, SCID, cytokines,
NF-AT, AP-1, Oct-1, NF-B, RAP1,
JUN, ICOS, cytokines, memory immunolog-
ical, immunization genetic; Lotzova E, Herberman
RB eds. 1990 Interleukin-2 and Killer Cells in
Cancer, CRC Press, Boca Raton, FL; structure of
IL-2 and its receptor: Rickert M et al 2005 Science
308:1477.
IL-3: This haematopoietic growth factor is a 28-kDa
glycoprotein secreted by CD4
+
lymphocytes, en-
coded in human chromosome 5q31. IL-3 is within a
Cell Membrane
Proteasome
degrades
Nuclear Membrane
Transcription
RNA
Chromosomal DNA
P P
NF-B
subunits
FADD
RIP
TRADD
TRAP2 p50
p50
p65
p65
IB
IB
MAPKKK
Figure I4. The action path of IB (Modified after T. Mariatis 1997 Science 278:818)
IL-3 957
I
gene cluster IL-3CSF2IL-13IL-4IL-5
centromere. IL-3 plays an important role in the
development of immunity to parasites by stimulating
the formation of hematopoietic effector cells. Togeth-
er with IL-13 they inhibit inflammation and boost
humoral immunity and IgE responses. interleukins,
hematopoiesis, IL-13, CIS, allergy; Craddock
BL et al 2001 J Biol Chem 276:24274.
IL-4: B-cell growth factor, 18-kDa glycoprotein,
encoded at human chromosome 5q31.1. It stimulates
the formation of immunoglobulins G and IgE. Its
receptor is encoded at 16p12.1-p11.2. The activation
of gene expression by IL-4 requires phosphorylation
of tyrosine, homodimerization and nuclear transloca-
tion of STAT6. IFN- and - inhibit IL-4 induced
activation of STAT6 and STAT6 induced genes partly
by inducing SOCS-1. IL-4 and IL-13 are implicated
in asthma and allergic reactions. interleukins,
immunoglobulins, IL-13, IL-3, STAT,
IFN, SOCS, asthma; Spitz H 1992 IL-4:
Structure and Function, CRC Press, Boca Raton,
FL; Kelly-Welch AE et al 2003 Science 300:1527;
IL-4 antagonist structure: LaPorte SL et al 2005 Proc
Natl Acad Sci USA 102:1889.
IL-5 (eosinophil differentiation factor): This is encoded
at human chromosome 5q31. IL-5R is expressed on
B lymphocytes, eosinophilic and basophilic granulo-
cytes. It is involved in the differentiation of B cells by
being associated with the syntenin protein that binds
transcription factor Sox4. IL-3, lymphocytes,
syntenin, allergy, Sox; Geijsen N et al 2001
Science 293:1136.
IL-6 (IFN-2/BSF-2): An interleukin group of proteins
(2128-kDa), encoded in human chromosome 7p21,
it binds to upstream DNA sequences in some genes.
Its receptor, IL-6R, is a transmembrane protein. IL-6
formation is induced by infection and primarily
mediates humoral immune reactions. The IL-6 pro-
moter contains GRE, AP-1, SRE and other transcrip-
tion factor-binding sites. The IL-6 receptor (IL-6R) is
trimeric and includes gp130 (918 amino acids,
encoded at 5q21), IL-6R chain (80-kDa, encoded
at 1q21) and IL-6. Its level is correlated with total
body fat; IL-6 and IL-1 deficiency together causes
hyperphagia and obesity in mice (Chida D et al 2006
Diabetes 55:971). interleukins, GRE, AP-1,
SRE, CRE, gp130, hepcidin; Marsch J et al
eds. 1992 Polyfunctional Cytokines: IL-6 and Lif,
Wiley, New York; MacKiewicz A et al eds. 1995
Interleukin-6-Type Cytokines, Annals of the New
York Academy of Science vol. 762.
IL-7 (lymphopoietin, 25-kDa): Stimulates lympho-
cyte precursors in the bone marrow. It is indispens-
able for normal proliferation of T cells. If the -chain
of the IL-7 receptor is defective in mice, D-J joining is
normal in immature B cells but recombination of the
distantly situated heavy chain V gene segments is
progressively impaired in proportion to their distance
from D-J. The Il-7 receptor ligands seem to signal for
the recombination by regulating the access of the
recombinase to the DNA. IL-7 promotes embryonic
neurons. It regulates antiviral CD4
+
T cell memory
(Lenz DC et al 2004 Proc Natl Acad Sci USA
101:9357). immunoglobulins, B cell, T cell,
TNF, osteoporosis; Tan JT et al 2001 Proc Natl
Acad Sci USA 98:8732.
IL-8: This activates neutrophils, cell migration, adhe-
sion, inflammation. SDF, melanoma growth-
stimulatory factor; Xie K 2001 Cytokine Growth
Factor Rev 12(4):375.
IL-9 (3239-kDa glycoprotein): An erythroid colony
stimulating factor that promotes (mast) cell prolifera-
tion and differentiation. The IL-9 receptor (522 amino
acids) is encoded in the pseudoautosomal region of
Xq28. But pseudogenes are found at 9p34, 10p15, 16.
p13.3 and 18p11.3 as well in the X and Y
chromosomes. IL-9R appears to be constitutively
expressed in Hodgkins disease and seems to be
involved in asthma. IL-9 appears to stimulate
myeloid leukemia. pseudoautosomal, Hodgkins
disease, pseudogene, mast cells, asthma,
T cell regulatory, leukemia; Demoulin JB et al
2001 Cell Growth Diff 12(3):169.
IL-10 (CSIF): This 18.5-kDa protein encoded at 1q31-
q32 is produced primarily by T
H
cells and acts as a
cytokine synthesis inhibitor, yet it may stimulate the
growth of mast cells and CD8
+
T cells. IL-10 is
involved in autoimmune diseases, protozoan, fungal
and bacterial infections and various carcinomas. Its
receptor (hIL-10R, 90110-kDa) is similar to the
interferon receptors and is encoded at 11q23.3. A
second receptor gene is in human chromosome 21.
IL-10 signals through the Jak-STAT and Tyk2
pathways. Gene therapy used for the alleviation
of inflammation seems promising. mast cell,
T cell, ICOS, signal transduction, osteopon-
tin, Tyk2; Moore KW et al 2001 Annu Rev
Immunol 19:683; Xing Z, Wang J 2000 Curr Pharm
Des 6:599.
IL-11 (23-kDa, encoded at 19q13.3): This controls
hematopoiesis in the bone marrow. Many of its
functions overlap with those of IL-6. The 43 kDa
IL-11 receptor, IL-11R1 chain is encoded at 9p13
close to IL-11R2. They recruit gp130 and gp190
glycoproteins and activate the Jak/Tyk cytoplasmic
tyrosine kinases. hematopoiesis, gp130, gp190;
Kaye JA 1996 Stem Cells 14 Suppl 1:274.
958 IL-4
I
IL-12 (interleukin-12): Aheterodimeric cytokine that is,
one of the most potent stimulators of T helper cells
(T
H
), natural killer cells (NK) and B lymphocytes, it
increases the production of interferon (IFN-). It is
produced by macrophages, neutrophils, dendritic
cells and B lymphocytes. The light chain (p35) is
encoded at human chromosome 3p12-q132 and the
heavy chain (p40) is at 5q31-q33.1. IL-12 receptor
(IL12R) deficiency causes susceptibility to infec-
tions. Microbial lipoproteins stimulate IL-12 produc-
tion by macrophages and the process is mediated by
Toll-like receptors. Nitric oxide synthase (NOS2) is
important in mediating signaling to IL-12. IL-12 is a
very promising tool in controlling HIV, Leischma-
niasis, malaria, tuberculosis, schistostomiasis and
other infectious diseases although some of its side
effects (toxic shock syndrome, atherosclerosis) may
limit its application. separate entries, osteopontine;
Lotze MTet al eds. 1996 Interleukin 12, Annals of the
New York Academy Science Volume 795; Picard C
et al 2002 Am J Hum Genet 70:336.
IL-13: The 131 or 132 amino acid protein is encoded at
human chromosome 5q31. It is a monocyte and
B lymphocyte regulator, synergistic with IL-2. It is
functionally related to IL-4 although the homology
between the two is about 20%. Unlike IL-4, IL-13 is
not a T cell proliferation factor. IL-13 receptor 1
subunit is encoded at Xq13. IL-3, IL-4, asthma;
Chiaramonte MG et al 1999 J Immunol 162:920.
IL-14: This is produced by activated T cells and B cell
lymphoma. T cell, lymphoma; Ford R et al 1995
Blood 86:283.
IL-15: A 114 amino acid T- cell growth factor,
encoded at human chromosome 4q13, is produced by
monocytes and epithelial cells. IL-15 induces the
proliferation of activated T cells and B cells. Along
with IL-2 it boosts the production of IFN and TNF.
T cell, monocyte, IFN, TNF, memory
immunological, chymase; Perera LP 2000 Arch
Immunol Ther Exp 48(6):457.
IL-16 (LCF, lymphocyte chemoattractant): This 130
amino acid lymphokine (M
r
13,500) is secreted by
activated CD8
+
cells, it binds to T cells by the CD4
receptor and suppresses HIVand SIV. HIV, SIV,
T cell; Cruikshank WW et al 2000 J Leukoc Biol
67(6):757.
IL-17 (CTLA-8): An interleukin with homology to
ORF13 of Herpes Virus Samiri (HVS). The human
IL-17 is a 20 to 30-kDa homodimeric protein. It
regulates cytokine and (leukemia) oncogene mRNA
stability. Along with IL-1, it is involved in the
activation of T cells and thus plays a role in
autoimmune arthritis (Nakae S et al 2003 Proc Natl
Acad Sci USA 100:5986). IL-17 producing CD4 T
cells form a separate lineage from the T
H
1 and T
H
2
helper cells and play a central role in inflammatory
responses (Harrington LE et al 2005 Nature Immunol
6:11213; Park H et al 2005 Nature Immunol 6:1133).
RORt orphan receptor directs the differentiation of
proinflammatory IL-17
+
TH cells (Ivanov II et al
2006 Cell 126:1121). CTLA, IL-1, IL-25,
arthritis, inflammation, T cells, T
H
, ROR;
Shi Yet al 2000 J Biol Chem 275:19167.
IL-18 (IGIF, interferon inducing factor): This is
produced by peripheral blood mononuclear cells,
dendritic cells, intestinal epithelial cells, osteoblastic
stroma cells and upon stimulation by monocytes,
macrophages (Kupffer cells). It has two different
immunoglobulin receptors. IL-18 enhances inflam-
matory responses but in cooperation with IL-12 it is
antiallergic. IL-18 activates natural killer lympho-
cytes, T
H
cells and the production of interferon . It is
a defense molecule against bacteria, viruses, some
fungal pathogens and protozoa. Along with IL-12 and
INF it may cause tumor regression. Its therapeutic
use, however, is hampered because of the toxicity of
cytokines and also because it leads to inflammatory
and autoimmune reactions. monocytes, killer
cell, T
H
, interferons, cytokines, Kupffer cell,
autoimmune disease; Nakanishi K et al 2001 Annu
Rev Immunol 19:423.
IL-20: A 176 amino acid homolog of IL-10, its
overexpression in transgenic mice is lethal. IL-20
binding activates STAT3 in keratinocytes. It is
upregulated in psoriasis. psoriasis, STAT, kera-
tin; Rich BE, Kupper TS 2001 Curr Biol 11:R531;
Blumberg H et al 2001 Cell 104:9.
IL-21: Along with its receptor (IL21R) IL-21 regulates
the clonal expansion of natural killer lymphocytes
and the production of immunoglobulins. autoim-
mune disease; Parrish-Novak J et al 2000 Nature
[Lond] 408:57; Ozaki Ket al 2002 Science 298:1630.
IL-22 (12q15): A cytokine of epithelial tissues which
mediates epithelial innate immunity when activated
by CD4
+
T cells and T
H
cells.
IL-23 (human chromosome 12): This is a heterodimeric
cytokine which shares a p40 subunit with IL-12. It
stimulates IL-17 and is critical for the inflammation
response of the brain and other tissues. IL-23 is
increased in tumors and upregulates matrix metallo-
protease MMP9, it increases angiogenesis and
reduces infiltration (tumor surveillance) by CD8 T
cells. In contrast IL-12 promotes tumor surveillance
as well as the cytotoxic effect of T cells (Langowski
JL et al 2006 Nature 442:461). IL-12, IL-17,
immunological surveillance, T cell, acanthosis,
IL-23 959
I
metalloproteinases; Aggarwal SWet al 2003 J Biol
Chem 2788:1910; Cua DJ et al 2003 Nature [Lond]
421:744.
IL-24: mda-7
IL-25: This is a suppressor of inflammatory responses
(Kleinschek MA et al 2007 J Exp Med 204:161).
IL-17
IL-32: An inducer of tumor necrosis factor , IL-1, IL-6
and IL-8, it appears to be involved in the inflamma-
tory pathway, including rheumatoid arthritis. TNF,
IL-1, IL-6, IL-8, rheumatoid fever; Kim S-H
et al 2005 Immunity 22:131; Joosten LAB et al 2006
Proc Natl Acad Sci USA 103:3298.
IL-33: This is an IL-1 like interleukin; its receptor is ST2
and it activates NF-B and MAP kinases. In vivo, it
induces the expression of IL-4, IL-5 and IL-13
(Schmitz J et al 2005 Immunity 23:479). IL-1,
IL-4. IL-5, IL-13, NF-B, MAP kinases
ILK (integrin-linked protein kinase): It phosphorylates
protein kinaseB, Akt and cyclins. protein kinases,
Akt, integrin, cyclins; Yamaji S et al 2001 J Cell
Biol 153:1251.
Illegitimate Child: Such a child is sired by a male other
than the legal father. This status can be ascertained by
DNA fingerprinting. The mother is always certain.
Illegitimacy, contrary to some myths, does not endow
the love baby with better abilities, despite some
famous examples (Leonardo da Vinci, Francis Bacon,
etc.). The out-of-wedlock children generally suffer
physical and emotional stress. Illegitimate offspring
in old pedigrees may confound recombination
frequencies, especially at tight linkage, it may cause
problems in prenatal diagnosis of some disorders, and
may frustrate genetic counseling. DNA fingerprint-
ing, prenatal diagnosis, genetic counseling
Illegitimate Insertion: Insertion elements may be
incorporated into the genome by a process that does
not require complete or even substantial homology
unlike general recombination events that usually have
the requisite of homology between the sites of
recombination. Restriction enzymes may facilitate
integration when it is non-homologous but do not
promote homologous insertion. illegitimate recom-
bination; Manivasakam P et al 2001 Nucleic Acids
Res 29:4826.
Illegitimate Pairing: Refers to the synapsis between not
entirely identical strands, which may lead to aberrant
crossover products. oblique crossing over, un-
equal crossing over
Illegitimate Recombination: Refers to recombination
when the synaptic strands are not or not entirely
homologous (microhomology). Insertion and trans-
posable elements are integrated by non-homologous
recombination and their target site shows minimal
homology. homologous combination, non-ho-
mologous recombination, non-homologous end-
joining, recombination, ectopic recombination,
Ku, DNA ligases, synapsis, RecA-indepen-
dent recombination, insertion element, transpo-
sable elements; Ehrlich SD et al 1993 Gene 135:161;
Hanada K et al 2001 J Bacteriol 183:4964.
Illumination: Various types of units of measurement are
in use. The most common unit is Lux = 1 standard new
candela from 1 m distance per 1 m
2
or it is measured
in watt or joule units. joule, watt, candela
ILTs (LIR, MIR, CD85, human chromosome 19q):
These are surface receptors on monocytes, macro-
phages, dendritic cells and B lymphocytes containing
immunoglobulin-like domains and most of them
carry ITIM sequences in the cytoplasmic side. ILT1
and ILT7 lack ITIM and are associated with ITAM
containing FcRI membrane adaptor protein.
ITAM, ITIM, FcRI; Volz Aet al 2001 Imunol
Rev 181:39.
Image Analyzer (image processor): This technique uses
video cameras with high light sensitivity, attached to
the microscope. The camera is connected to a
computer that can further enhance the image recorded
by the camera. Thus it can electronically enhance (by
digitalization) and process the image and can detect
details that cannot be perceived by directly viewing
through the microscope. The electronic system may
show the picture in false colors, i.e., selected by the
operator rather than the natural color of the object.
The use of such devices can rid the image of
background noise and greatly enhance its clarity.
In addition, the operators eyes are not stressed.
The tissue-specific distribution and expression of the
bacterial luciferase transgene can be monitored by the
microchannel plate enhanced photon counting analy-
zers. This set-up consists of a microscope, an image
processor, a TV monitor and a computer. The heart of
the equipment can be outlined as:
MICROSCOPE !photocathode
!microchannel plates
!phosphor screen !DISCRIMINATING
VIDICON
This system can resolve a single photon. By
comparison a single native bacterial cell releases about
10,000 photons. Image analyzer (e.g., VAX Station
II/GP4) is also used for scanning DNA fingerprint
autoradiograms. microscopy, luciferase
960 IL-24
I
Image Clones: These are gridded sequences verified
(Research Genetics: http://www.resgen.com/) or not
sequence verified human and other gene clones, gene
clusters, suitable for microarray hybridization. Uni-
Gene, microarray hybridization
Image Processing: image analyzer
Imaginal Disks: After fertilization of the Drosophila
egg, the zygote nucleus begins to divide within a
common cytoplasm and forms a syncytium
(a multinucleate protoplasm) without actual separa-
tion by cell membranes. After about 2 h and almost 13
divisions the cellular blastoderm stage is reached
(around 6,000 cells). Then the cells move to the
periphery of the embryo and the yolk occupies the
central space. Within less than 24 h the larva is
hatched and this developmental stage (3 instar steps)
lasts for about 4 days. Inside the larva some groups of
cells, distinguishable by location, shape and size, the
imaginal disks (50,000 cells) are set aside for serving
as initials for the various organs and structures of the
adult organism. The larva does not use the imaginal
disks and removal of these disks does not kill the
organism. As the larva is metamorphosed into pupa
most of the larval tissues disintegrate to support the
development of the differentiation from the disks.
During pupation, from these prefabricated ele-
ments, the imago is assembled by cell and tissue
fusions. From the anterior (front) part the head, from
the middle region the thorax and from the posterior
(hind) part the abdomen develop. If the imaginal
disks are removed from their original position after
the 3rd instar stage (about 5 days) and grafted into a
new location of another larva, these disks develop
into an extra eye, a wing, a leg or other structures,
depending on which imaginal disk has been chosen
for the surgery and not on the host tissue. Thus, in the
imaginal disks developmental determination is com-
pleted much before the onset of morphological and
functional differentiation. For correct differentiation
it is necessary that the transplant is done in a larva and
not in an adult. In the abdomen of an adult the disks
only proliferate. After a series of transfers through
adults, the original determination of the disks may
change, and when the proliferated disk tissue is
transplanted into a larva, an antennal disk may lead to
the development of a leg instead. This altered course
of differentiation is called transdetermination. The
path of transdetermination is not accidental or ran-
dom. For example, a genital disk may develop into a
proboscis (mouthpart) or may pass through some
indirect steps in a certain order such as genitalia
proboscis antenna leg. Awing from the genital
disk cannot be formed directly but may develop
through an antenna or a leg. The process of transde-
termination is only a change in competence for
differentiation without a mutational change whereas
in homeotic mutants one structure is replaced or
altered after a change in the DNA. Drosophila,
morphogenesis, homeotic genes, development,
fate maps, determination, proboscis, antenna,
blastoderm, homeotic mutants; Ramirez-Weber
F-A, Kornberg TB 2000 Cell 103:189.
Imaging: New technologies (fMRI, tomography, endo-
scopic confocal microscopy) permit scanning of the
whole body to monitor the turning on of genes and
followmetabolic processes (including activities in the
brain), stages of cancer and its metastasis, without
sacrificing the animals or invasive examination of
humans. The use of [
18
F] fluorodeoxyglucose is
selectively done by cells of high glucose metabolism
(cancer) and facilitates the identification of malig-
nancy when used with tomography (FDG-PET).
Vascular cell adhesion molecule (VCAM) can be
used to reveal increased angiogenesis in cancer.
Radio-labelled Annexin V and TRAIL can reveal
apoptosis. The anti-tumor efficacy of epothilones
(spindle-fiber poisons) can be detected. nuclear
magnetic resonance spectroscopy, microscopy,
image analyzer, tomography, angiogenesis,
annexin, TRAIL, VCAM, epothilone;
Swedlow JR et al 2003 Science 300:100; Weisssleder
R 2006 Science 312:1168.
Imago: Refers to the adult form of an insect either male
or female (see Fig. I5). Drosophila, imaginal disk
Figure I5. Imago
Imatinib: Gleevec, Desatinib
Imbibition: Refers to the absorption of water or other
liquids.
IMC: Denotes intramolecular chaperone. chaperone
ImerslundGrasbeck Syndrome: This refers to megalo-
blastic anemia (MGA1).
Imidazole: This is present in many organic molecules
and may mediate tautomerism. Src, tautomeric
shift (see Fig. I6).
Imidazole 961
I
N
N
H
Figure I6. Imidazole
Imino Form: Refers to a type of an amino acid that arises
from an amino form according to the following
reaction:
NH
2
CCOOHflavin !NHCCOOHflavinH
2
AMINO -IMINO
Similar transformation can take place in nucleo-
tides and can facilitate unusual hydrogen pairing
between bromouracil and guanine or cytosine and
adenine. hydrogen pairing
Iminoaciduria: Proline and hydroxyproline use the
semi-recessive renal glycine reabsorption mechanism
and when it fails these amino acids accumulate in the
urine. aminoacidurias
Iminoglycinuria: In this condition excessive proline and
hydroxyproline are present in the urine. This is
probably due to heterozygosity of hyperglycinuria.
hyperglycinemia
Imitatory Epigenotype: This theory assumes that the
functional units of the phenotype are genetically
modular and integrated within the group and
relatively independent of the rest of the phenotype.
It can be studied by the statistical methods used for
QTL. QTL; Mezey JGet al 2000 Genetics 156:305.
Immediate Early Genes: These early genes of a virus are
first turned on after infection without any requirement
for synthesizing virally encoded proteins. delayed
early genes, late genes
Immobiline: Precast gel strips for first-dimensional run
in two-dimensional gel-electrophoresis.
Immortalization: Denotes that a cell in a culture will not
senesce but will proliferate indefinitely. Normally,
cultured cells die but cancerous transformation or by
fusing normal cells with a cancer cell makes them
immortal. Immortalization and tumorous growth
are, however, under separate genetic control. Cells of
the germ line are also practically immortal because of
their transmission from generation to generation until
the extinction of the strain. hybridoma, cancer,
telomeres, p16
INK
; Tevethia MJ, Ozer HL 2001
Methods Mol Biol 165:185.
Immune Clearance: Refers to the destruction of
infecting foreign cells by the phagocytotic activity
of various special lymphocytes. Its major sites are in
the liver, and to a lesser degree in the spleen but other
tissues with phagocytotic activity may also perform
this function. The C3 complement and its receptors,
C5b-9 and IgG, are important factors. complement,
immunoglobulins
Immune Deviation: In non-atopics postnatal exposure to
inhalant allergens may redirect the fetal immune
response toward the T
H
1-like cytokine pattern.
atopy, allergen, allergy, asthma
Immune Evasion (immune escape): Some viruses may
inactivate the MHC class I antigen presentation
system and thus escape the attention of the cytotoxic
T lymphocytes (CTL). Nevertheless, the killer cells
(NK) may destroy the invader. Herpes simplex
viruses may inactivate or interfere with the TAP
transporters and various subunits of the proteasomes.
In HIV-infected human cells the peptide epitopes of
the virus may mutate and rather than being a ligand
they may serve as Tcell receptor antagonists resulting
in the inactivation of the HIV-specific T cells. Some
adenoviral glycoproteins immobilize the MHCclass I
molecules to the endoplasmic reticulum. Some
cytomegaloviruses (CMVs) make proteins that bind
to the MHC class I molecules and dislocate the
heavy chains into the cytosol (from the endoplasmic
reticulum) and thus the proteasomes destroy them.
Another trick of some viruses to mediate the
internalization and thus inactivation of the MHC I
proteins. CMVs may produce their own MHC class I
homolog proteins (UL18, m144) that help evade
natural killer cell attacks on the virus. These protein
homologs may regulate the immune system in
various other ways as well. CMV may also down
regulate the synthesis of the MHC II type molecules
involved in the B lymphocyte defense system.
An IL-10 homolog encoded by the Epstein-Barr
Virus (EBV) may interfere with T cell function. The
inhibition of the mRNA translation of the virus-
encoded antigen limits antigen presentation on the
MHC class I molecules to CTL (Yin Y et al 2003
Science 301:1371). Viral IL-10 homologs may
subvert the IL-12-regulated interferon, cytokine and
TAP production. Some viruses may interfere with the
process of apoptosis, used by the organ to pathogen
infected cells before the maturing infective viral
particles could be released. Staphylococcus bacteria
secrete poly--DL-glutamic acid (PGA) to facilitate
growth and survival in human hosts. PGA shelters
S. epidermidis an opportunistic hospital-acquired
pathogenagainst host antimicrobial peptides and
neutrophil phagocytosis (Kocianova S et al 2005
J Clin Invest 115:688). Some bacteria and viruses
modulate the surface structures (inhibit the comple-
ment of the host or display antigenic variations) in
order to avoid recognition. The pathogens may
activate or interfere with the Toll-like receptor
962 Imino Form
I
(TLC) signaling pathway. Host receptors may be
degraded, antigen presentation may be inhibited, cell
surface molecules may be modulated, etc. immune
system, antigen presenting cell, epitope, anti-
microbial peptides, neutrophil, MHC; T cell;
MICA; Kavanagh DG et al 2001 J Exp Med 194:967;
Groh V et al 2002 Nature [Lond] 419:734; common
and specific principles of immune evasion by viruses
and bacteria: Finlay BB, McFadden G 2006 Cell
124:767.
Immune Homeostasis: After an immune reaction the
immune system is reset to the pre-immunization state
and can then respond to a new antigen. immune
system
Immune Privilege: Grafts to certain sites (eyes, testes,
brain) may be protected from rejection caused by the
constitutive expression of the Fas ligand (FasL).
Other factors may be blood tissue barriers, direct
secretion of the tissue fluid into the blood, absence of
efferent lymphatics, potent immunosuppressive envi-
ronment (TGF), reduced expression or induction
of MHC, neuropeptides, -melanocyte-stimulating
hormone, vasoactive intestinal peptide, calcitonin
gene-related peptide [CGRP], and membrane-bound
inhibitors of the complement activation and fixation.
Immune privilege may be necessary for pregnancy,
for avoiding certain diseases and graft rejection, etc.
TGF, Fas, MHC, calcitonin, complement;
Rall GF et al 1995 J Exp Med 182:1201; OConnell J
et al 2001 Nature Med 7:321.
Immune Response: The response is mounted by the
body against foreign invaders. It may be triggered by
sensing some surface architectural elements of the
invader (stranger hypothesis) or by stress signals
emanating from the cells/tissues in the stressed body
(danger hypothesis). Such signals may be conveyed
by uric acid crystals, which are degradation products
of nucleic acids. The dendritic cells then present
the foreign antigen to the CD8
+
T lymphocytes.
The dendritic cells can also recognize the infectious
agents by their Toll-like receptors and migrate to the
lymphoid organs and secrete interleukin-12 (IL-12).
Here they encounter CD4 T cells which can develop
into either Th
1
or Th
2
helper T cells. The Th
1
lymphocytes secrete interferon- and mediate immu-
nity against viruses or bacteria. The Th
2
effector cells
use interleukin-4 (IL-4) to protect against multicellu-
lar pathogens or allergens. Correct recognition is
important because inappropriate reaction may result
not only in lack of protection, but also in autoimmune
disease or allergy. In the activation of the Th
1
cells the
four Notch receptors and their five ligands play a key
role under the influence of the RBPJ transcription
factor (a mammalian homolog of the Drosophila
Suppressor of Hairless [Su(H))]. If RBPJ is reduced
or absent (in mouse cells) Th
2
development is
favored. MHC, immune system, glycans;
Heath WR, Carbone FR 2003 Nature [Lond] 425:
460; Shi Y et al 2003 Nature [Lond] 425:516;
Amsen D et al 2004 Cell 117:515; Tanigaki K et al
2004 Immunity 20:611.
Immune Selection: Refers to the process by which
pathogens are capable of evading or resisting the host
immune system.
Immune Suppression: Refers to the removal or inacti-
vation of the antigen. This can be achieved by
destroying the target cells by CTL, B cells, macro-
phages or killer cells or by cytokines and other
immunosuppressive agents. An immunosuppressive
drug reduces the bodys ability to mount an immune
response and defend against foreign antigens. Contra-
suppression prevents suppression and allows for the
development of immunity. immune tolerance,
CTL, killer cell, veto cell; Takemoto SK 2000
Clin Transpl 481.
Immune Surveillance: immunological surveillance
Immune Synapse: On the surface of natural killer Tcells
(NK) inhibitory immunoglobulin-like receptors
(KIR1, KIR2) occur that cause clustering of HLA-C
molecules at the surface of the target cells. At the
target and the NK cells HLAKIR forms rings
around the intercellular cell adhesion molecules and
lymphocyte-associated antigen-1 for about 20 min-
utes. Multiple such synapses may occur as the Tcells
invade the selected target. Synapse formation re-
quires the reorganization of the cytoskeleton of the T
cells and the antigen-presenting cells. killer cell,
KIR, HLA, antigen, agrin, cytoskeleton,
antigen-presenting cell; Khan AA et al 2001
Science 292:1681; Dustin ML, Coper JA 2000
Nature Immunol 1:23; van der Merwe PA, Davis SJ
2002 Science 295:1479.
Immune System: Refers to a complex defense organi-
zation of vertebrate animals. The main cellular
components of the immune system are the lympho-
cytes and macrophages. B lymphocytes synthesize the
antibodies that react and destroy the foreign antigens.
T lymphocytes generate the antigen receptor-MHC
protein complex that specifically recognizes indi-
vidual antibodies and is involved in the destruction
of foreign antigens (see Fig. I7). Lower animals may
use phagocytosis as defense. Plants do not have an
immune system like animals yet they also have
pathogen-associated molecular mechanisms for recog-
nition by the so-called elicitors. Some of the elicitors
are peptides. A 23-amino acid peptide of Arabidopsis
(AtPep1) activates the transcription of the defensing
Immune System 963
I
gene (PDF1.2) and the synthesis of H
2
O
2
. The pre-
cursor of the peptide (92 amino acids) can be induced
by wounding, methyl jasmonate and ethylene. There
are 6 paralogs of PDF1.2 in Arabidopsis and orthologs
occur in other plant species (Huffaker A et al 2006
Proc Natl Acad Sci USA 103:10098). The AtPep1
receptor also functions in transgenic tobacco plants
(Yamaguchi Y et al 2006 Proc Natl Acad Sci USA
103:10104).
The immune system protects the body from
microbial infections and also from non-infectious
foreign macromolecules such as proteins, polysac-
charides and tissue grafts.
Smaller foreign molecules (haptens) may also
trigger the immune system primarily when associated
with proteins. The molecules that elicit the immune
response are called antigens. Antigens stimulate the
formation of antibodies which are the actual defense
molecules. The immune reaction is extremely
specific and minute differences between antigens,
such as single amino acid substitutions or isomers
may be particularly recognized. The immune system
distinguishes the bodys own antigens from those of
extraneous origin. The absence of an immune
response to the bodys self antigens is known as
acquired immunological tolerance. The tolerance,
i.e., distinguishing self from foreign molecules
develops in the thymocytes by negative selection of
self-reacting T cells. The T cell antigen receptor
controls the activation and subcellular localization of
Ras and MAPK signaling intermediates and by a
subtle margin and thus develops self-tolerance
(Daniels MA et al 2006 Nature [Lond] 444:724).
The immature immune system may learn to ignore
even a foreign antigen if exposed to it at a very early
stage. Immunological tolerance may be produced in
the later stages of development with immunosup-
pressive drugs, by very high or repeated exposure to
extremely low amounts of the foreign antigen. Also,
altering the so-called antigen-presenting cells may
affect tolerance. These antigen-presenting cells bind,
process and combine foreign antigens with Class I
and II proteins of the HLA complex (MHC).
T lymphocytes can be made tolerant to foreign
antigens more readily than the B cells. In some rare
autoimmune diseases even self-discrimination may
break down with very serious consequences for the
individual because the defense system of the body
may destroy its own tissue. The key players in
mounting an immune response are approximately two
trillion lymphocytes (white blood cells) of the human
body. B lymphocytes are involved in the humoral
(circulating in the blood) immune response. B cells
produce antibodies. These are called B cells because
they are produced in the bursa of Fabricius (intestinal
pouches) in birds. In humans, B cells originate from
the stem cells of the fetal yolk sac, then in the liver
and finally in the bone marrow (humans do not have a
bursa). The pre-B cells appear in the fetal liver by the
8th week of gestation and contain immunoglobulin
chains in their cytoplasm but not on their surface.
About 2 weeks later B cells appear. By the 13th week
B cells have immunoglobulin on their surface. By
the 12th week B cell production shifts to the bone
marrow. IgD (immunoglobulin ) appears by the 14th
week in the spleen, lymph nodes and blood. After the
14th week HLA antigens begin to appear. As the
antibody gene rearrangements proceed all other
immunoglobulin genes may be expressed (see Fig.
I8). The proliferation and differentiation of B cells
requires the presence of antigens on their surface and
some soluble factors obtained from the T cells. The
T
H
(helper) and T
S
(suppressor) cells regulate the
development of B cells.The activation of helper T
cells requires the presence of APC cells (antigen-
presenting cells), HLA Class I and II proteins and
interleukin-1. The T
H
cells secrete some mediators (e.
g., lymphokines).
The activated lymphocytes and mediators then
induce the formation of receptors that is followed by
the proliferation and differentiation of both T and B
lymphocytes. The suppressor lymphocytes may
prevent the induction of the immune response by
exposure to a wide variety of molecules. Important
representatives of the immune system are T lympho-
cytes (shaped in the thymus), their primordia develop
by the 5th-6th week of human gestation and the
first mature T cells appear by the 9th-10th week (see
Fig. I9). T cells are involved in the cell-mediated
immune response, i.e., they react with antigens bound
to their surface. As the maturation of the T cell
precedes the CD antigens (CD1, Cd2, CD4, etc.)
appear on their surface and identify Tcell subsets. By
the 16th-20th week the spectrum of subsets reaches
that of adults. T cells usually respond to antigens
in association of the HLA complex (MHC, major
histocompatibilitycomplex). Tcells withCD8antigens
respond to Class I proteins of the HLA complex
whereas CD4 T cells are limited to HLA Class II
proteins (DP, DQ, DR). This phenomenon is called
Fetal
liver
Bone
marrow
Thymus
Lymphoid
organs
T cells Cellular immunity
Humoral immunity
(antibodies)
B cells
Figure I7. Development of the immune system and major components
964 Immune System
I
MHC restriction. Maternal IgG may cross the placenta
after the 16th week and provides early immune
protection for the fetus. Fetuses and newborns may
not respond much to foreign cells because lymphocyte
development may be arrested when contacted by
antigens and anti-idiotype antibodies. IgM and IgA
are normally (in the absence of infection) not present in
substantial amounts in newborns. Although after birth
the maternal IgG tends to be eliminated, it is gradually
replaced by the infants own antibodies. By the age
of 3, IgG levels become sufficient. Before the end of
the first year IgM levels reach those of adults but
IgA levels rise very slowly, reaching adult levels
only by 912 years of age.The appearance of the
immune reaction is the result of a developmental
process. The virgin T cells (that have never been
exposed earlier to a specific antigen) become
effector cells, i.e., they begin to proliferate and
produce either the cell-mediated (T cell) or the
humoral (B cell) response. Some other lymphocytes
are also induced to proliferation and differentiation.
This time they do not participate in the immune
response but become memory cells that will
remember the same antigen by virtue of their
differentiation, and assume the effector cell role later
on similar exposure (clonal mechanism of secondary
immune response).
The immune response is mounted relatively slowly
(in days or weeks) when exposed to a particular
antigen for the first time (primary immune response)
but on subsequent exposures the response is faster
because of the availability of memory cells. This
phenomenon forms the basis of immunization
(vaccination) as it is used in medicine. In order to
generate an immune response the lymphocyte
receptors must be exposed to an antigen. This is
Released antibodies
Plasma B cell
C
e
l
l

n
u
c
l
e
u
s
J Chain
J Chain
IgM Pentamer
Killer T
Antigen-presenting
cell
T
H
T
S
TCR
IgA Dimer
Memory cell
H
e
m
a
t
o
p
o
i
e
t
i
c

c
e
l
l
Immature
T cell
Thymus
Differentiating T cell
T
c
r

c
o
m
p
l
e
x
Virgin
B cell
Figure I8. Development of the immune system and its major components. The B and T lymphocytes in mature individuals
are generated by the hematopoietic cells in the bone marrow. The virgin B cells become either plasma cells or memory cells
upon the encounter of a foreign antigen and lymphokines. As a response the plasma cells manufacture antibodies that are
first embedded in the plasma membrane of the B cells, and when the membrane is saturated, they are released as
circulating antibodies. Antibody IgMpolymerizes intoa pentamer and joins AJ peptide chain. The IgAantibody forms a dimer
and A J polypeptide chain also braces it. The memory cells do not become active until follow-up exposure to the particular
antigen. Each of the antibody-producing cells makes one single type of antibody and its clonal progeny also makes the same
antibody. Different antibodies are made by different B cell clones. the immature T cells differentiate into T cells within the
thymus. The thymus is a bilobate organ that develops in the embryo and it reaches its maximal function during puberty and
then begins a gradual, slow decline, accompanied by a decrease of T lymphocyte production and a weakened immune
response. The mature T cells are of three main types: killer cells (cytotoxic T lymphocytes, CTL), helper T cells (T
H
) and
suppressor Tcells(T
S
). Thespecificityof theTcell functiondependsonthesurfaceantigenscarriedbytheantigen-presenting
cells. TheTCR(Tcell receptor) hassubstantial structural andfunctional homologywiththeimmunoglobulinproteins. TheTCR
complex is formed by the participation of the MHC protein, encoded by the HLA complex and a series of cell membrane
proteins. The killer cells destroy the membranes of the invading cells, followed by lysis of their content
Immune System 965
I
usually followed by the signals of cytokines and other
co-stimulator molecules (CD40, CD80, CD86 on the
antigen-presenting cells) resulting in the clonal
proliferation of specific lymphocytes and memory
cells. Contact of CD28 and CD80, CD86 initiates the
immune response and the CTLA-4 receptor with
CD80, CD86 terminates the Tcell immune reactions.
CD28 also stimulates the synthesis of the Bcl anti-
apoptosis proteins or B cells. The C3d component of
the complement in association with the CD21
complement receptor is the co-stimulator. In case
the antigen cannot reach the lymphocytes or the co-
stimulatory response is defective there will be no
immune response. The immune system is largely
associatedwith lymphnodes and the spleenand as such
represents systemic responses. Some of the immune
reactions are, however, localized to specific tissues
such as the gut epithelia or intraepithelial lymphocytes.
In insects, different types of peptides such as
cecropin (3539 amino acids), defensin, attacin,
diptericin (82 amino acids), drosopcin, metnikowin,
drosomycin, andropin and lysozyme mediate the
humoral defense system. In addition, cellular re-
sponse (phagocytosis) may also be available. A
genome-wide survey of the Drosophila genome
(13,197 genes tested) using microarray analysis
revealed that microbial infection induced 230 genes
and repressed 170. A different defense system occurs
in plants. The molecules (virulence factors) of the
invading pathogens act as elicitors for the production
of host proteins. These proteins may cause basic
changes in the plant metabolism. In extreme cases the
hypersensitive reaction kills the infected plant cells
to prevent the spread of the disease throughout the
entire plant body (Nimchuk Z et al 2003 Annu Rev
Genet 37:579). antibody, immune response,
IL1 IL 12
IL1 IL8
IL1 IL8
Macrophage
Neutrophil
Basophil
IL6 IL 15
IL1 IL 10 IFNg
IL2 IL 13 TNFa
IL4 IL 14 TNFb
IL6
IL 10
IL 4
IL = Interleukin, INF = Interferon, TNF = Tumor necrosis factor
IL10 TNFa
IFNa TNFa
TNFa
TNFa
TNFa
IFNb
IL1 IL 10 IFNa IL1 IL 13 IFNg
IL1 IFNg
IL4 TNFb
IL8
IL4
IL5
IL3 IL4 IL5
IL1 IL4
IL2 IL9
IL4 IFNa
IL6 IFNb
IL8 IFNg
IL3 IL8
Eosinophil
Tlymphocyte
IL3 IL4
IL4
IL4 IL5
IL9
IL10
IL10
Mastcell
TL3 TNFa
IL3 IFNa TFNa
IL4 IFNb TNFb
IL1 IL12 TNFa
IL6 IFNa TNFb
IL10 IFNb
IL6 IL2 IFNb
IL8 IL15 TNFa
IL10
IL10 TNFa
B lymphocyte
IL12 TNFb
TNFa
TNFb IFN
IFNb
IL1
Figure I9. Some types of communication in the immune system
966 Immune System
I
immunoglobulins, HLA, Tcells, TCR, sur-
rogate chains, B cells, autoimmune disease,
complement, lymphokines, phagocytosis,
hapten, antigen, MHC, antigen-presenting
cell, blood cells, lymphocyte, lymphocyte
homing, interleukin, immune system diseases,
innate immunity, memory immunological,
CD80, CD40, CD28, complement, CD21,
apoptosis, immune evasion, immune tolerance,
leukalexins, host-pathogen relations, xeno-
transplantation, molecular mimics, bystander
activation, allergy, asthma; Abbas AK Janeway
CA 2000, Cell 100:129; Janeway CA Jr 2001 Proc
Natl Acad Sci USA 98:7461; Germain RN 2001
Science 293:240; Di Gregorio E et al 2001 Proc Natl
Acad Sci USA 98:12590; plant immune system:
Jones JDG, Dangl JL 2006 Nature [Lond] 444:323;
killer cells; immunoglobulin receptors; MHC; alloan-
tigens: http://www.ebi.ac.uk/ipd.
Immune System Diseases: agammaglobulinemia,
DiGeorge syndrome, Wiskott-Aldrich syndrome,
Reiter syndrome, arthritis, lupus erythemato-
sus, celiac disease, immunodeficiency, Sjgren
syndrome, autoimmune diseases
Immune Tolerance: Refers to the failure of the immune
system to respond to antigen(s) by supposedly
suppressing the alloreactive Tcells. The earlier belief
was that neonates were supposed to exhibit immune
tolerance, however, recent research has indicated that
their immune response may be different. Immune
tolerance is regulated either by anergy or by
suppression. Suppression may be mediated by low
oral doses of antigens or by clonal anergy when high
doses of the antigen are provided. Oral tolerance may
extend to tolerance of the gut immune system and
may thus exhibit a systemic immune reaction to
ingested proteins. The brain-blood barrier prevents
lymphocytes from entering the central nervous
system. The peripheral immune tolerance may
include T cell-activated repression by the secretion
of TGF-. Both CD4 and CD8 regulatory T cells
control and can transfer donor-specific tolerance for
allografts (Sho M et al 2005 Proc Natl Acad Sci
USAS 102:13230). It is somewhat baffling why
allogeneic fetuses are not rejected by the maternal
immune system. The mothers body may reject organ
transplants from the child because of the paternal
genes of the offspring. Notwithstanding, the same
mother can carry to term the child. It has been
hypothesized that either physical separation or
antigenic immaturity of the fetus or some sort of
immunological inertness of the mother toward the
conceptus may be responsible. It appears that the
maternal T cells specific for paternal MHC class I
alloantigens are reduced during pregnancy. The
observation that the concentration of tryptophan is
lower in the maternal-fetal interface tissues led to
the experimentally supported assumption that trypto-
phan may be required for T cell proliferation.
The level of tryptophan is reduced by indoleamine
2,3-dioxygenase (IDO). The inhibition of IDO by
higher doses of tryptophan analog 1-methyltrypto-
phan reduced the maintenance of allogeneic concepti
in mice apparently by curtailing the chances for Tcell
mediated rejection. The loss of autoimmunity may
occur after infection by pathogens due to molecular
mimicry, epitope spreading or bystander activation.
B cell tolerance may be lost after removal of the
self-antigen or when T cell help is provided at the
initial exposure but not if the T cell is available after
the exposure to the self-antigen. In tissue or organ
transplantation generally immunosuppressive drugs
are used. However, these drugs themselves present
health risks. Research is underway to find ways of
minimizing the immune reaction to foreign proteins
(Waldmann H, Cobbold S 2004 Science 305:209).
Some tumors avoid destruction by induction of
T cell tolerance (Willimsky G, Blankenstein T 2005
Nature [Lond] 437:141). antigen, anergy, mast
cell, immunoediting, TGF, mucosal vac-
cines, T cell, T cell receptor, T cell regula-
tory, thymus, immune system, self-tolerance,
immunosuppression, alloreactive, immunity,
Rh blood group, incompatibility, conceptus,
bystander activation, epitope, molecular mi-
mics, transplantation in utero; Krensky AM 2001
Pediatr Nephrol 16:675; Godnow CC 2001 Lancet
357:2115; Robertson SA, Sharkey DJ 2001 Semin
Immunol 13(4):243; Moffett-King A 2002 Nature
Rev Immunol 2:656.
Immunity: Refers to a protected state against biological
(microbial) or other agents. Natural immunity is the
readily emerging incompatibility between donor and
recipient tissues. The xenoreactive natural (human)
antibodies (XNA) react with the Gal13Gal termi-
nal antigens present on the endothelial lining of blood
vessels of the xenografts of the majority of mammals
(except humans and some primates). This binding
then activates the human complement system. The
graft complement decay accelerating factor (DAF),
membrane cofactor proteins (MCP) and CD59
cannot neutralize the host natural immunity reaction
and thus rejection may be initiated. Further injury to
the graft is inflicted by the natural killer cells of the
host. Although NK cells normally carry inhibitory
receptors that usually prevent an attack on MHCclass
I molecules but this system may also fail with the
MHC system of the graft. Acquired immunity
develops as a reaction of the immune system of the
organism. The transfer of antibodies or activated
Immunity 967
I
lymphocytes from another body conveys passive
immunity. Natural immunity means that the cells are
not susceptible to a particular organism, e.g., humans
are not infected by wheat rust. Genetic or familial
immunity indicates that a group of individuals is
resistant to or free of a particular type of infection. In
maternal or intrauterine immunity humoral antibo-
dies pass through the placenta into the fetus. Cell
mediated immunity is the result of T lymphocyte
activation by adoptive transfer (adoptive immuniza-
tion) of an immune donor to syngeneic recipients.
Humoral immunity is provided by the antibodies
secreted by B lymphocytes. In neonate immunity IgG
immunoglobulins are secreted by the mothers milk
with the assistance of the FcRn receptor. At the
newborn stage monocytes and macrophages have
limited activity resulting in the reduction of the MHC
class II proteins, co-stimulatory molecules, antigen
processing and cytokines. Natural killer cells are
present but not very active. Phage immunity describes
the condition where a lysogenic bacterium cannot be
superinfected by another bacteriophage. immune
response, antibody, humoral antibody, MHC,
FcRn, lymphocyte, superinfection, mucosal
immunity, syngeneic, xenotransplantation,
complement, killer cells, immune tolerance,
MHC, cytokines, antigen-presenting cell,
killer cells
Immunization: Refers to the induction of immunity. It
can be active immunization by introducing specific
antigens into the body to promote the formation of a
specific antibody or passive immunization by intro-
ducing antibodies into the body that may provide
temporary immunity. Vaccination involves the intro-
duction of live (attenuated) or killed microbes into the
body either through the bloodstream or by oral
means. The bonding subunit of E. coli heat-labile
enterotoxin (LT-B) is a very effective immunogen.
Bacterial polysaccharide vaccines are not effective in
infants before 1824 months of age although protein
conjugates may be effective in few weeks old
neonates. At this stage attenuated live viral or
bacterial vaccines are usually not advisable. The
results of DNA immunization at the early stages of
life are still debated.
Transgenic plants encoding LT-B, express the
foreign peptides, and are able to bind the natural
ligand after oligomerization. Mice fed by antigens
produced by transgenic plants can be orally immu-
nized. Also, tobacco plants transgenic for murine
antibody chain, hybrid immunoglobulin A - G
heavy chain, an immunoglobulin J chain and a rabbit
secretory component, respectively, after intercrossing
produced segregating progeny that simultaneously
expressed all four polypeptides. The polypeptide
chains were successfully assembled within the
transgenic hybrid into a functional high molecular
weight secretory immunoglobulin that could recog-
nize streptococcal surface adhesion molecules. Inter-
estingly, in plants this process can take place in a
single cell whereas in animals it requires two cell
types. The results indicate the possibility of using
immunoglobulins manufactured by plants for oral
vaccination. In reactive immunization the antigen
is so highly reactive that a chemical reaction takes
place at the site of the combining antibody. This
mechanism may enhance catalytic antibody chemis-
try. The common type of immunization does not
result in covalent interaction between the antigen and
the antibody. Although sharks can synthesize a
variety of immunoglobulins (somewhat different
from higher mammals) they cannot be immunized.
antibody, immunoglobulins, immunization ge-
netic, vaccines, transformation genetic [transfor-
mation of plants], intercellular immunization,
intracellular immunization, immunization in
vitro, memory immunological
Immunization, Genetic (DNA vaccination): Involves
introducing into an animal (or into a specific animal
tissue) a gene or expression gene library encoding a
particular antigenic protein(s) by biolistic transfor-
mation or plasmid vectors resulting in antibody
production. The transgene is introduced into muscle
tissue or into the skin. The latter, especially when
associated with lymphoid tissues, is more suitable
because it harbors a greater number of antigen-
presenting cells. This method does not involve the
risk of live or attenuated pathogen vaccines. Target-
ing antigen-ligand (L-selectin or CTLA-4) constructs
to the lymph nodes or to antigen-presenting cells
(dendritic cells, macrophages and lymphocytes)
enhances the effectiveness of DNA immunization
100 to 1000 fold. They may elicit Th1 or CD4
+
and
CD8
+
Tcell responses. The presence of special DNA
sequences (IL-2) may serve as adjuvants and
substantially magnify the reaction. Poly G:C or poly
I:C or palindromic (5-GACGTC, 5-ADCGCT, 5
AACGTT) sequences may effectively induce the
production of interferons and interleukins, potent
stimulants of the killer effects of lymphocytes. Co-
injection of vectors containing mutant caspases
stimulates T and B lymphocyte responses. DNA
vaccination appears to be effective for infectious
diseases, malaria, autoimmune diseases, cancer and
also for proteomic research. DNA-based vaccines,
encoding syngeneic or allogenic, lectin-like natural
killer cell ligands (NKG2D) along with survivin or
carcinoembryonic antigen activate both innate and
adaptive antitumor responses (Zhou Het al 2005 Proc
Natl Acad Sci USA 102:10846). The goal of this
968 Immunization
I
procedure in the case of cancer is not prevention but
the cure of tumors already present in the body. A
potential advantage of DNA vaccination versus
protein vaccines is the continuous expression of the
antigen. DNA vaccines are expected to be processed
for immune recognition by the cells special protein
degradation system, have high temperature-stability,
and the cost may be low. A possible slight risk is that
the transgenic products may have adverse side effects
such as inducing autoimmune reaction or immune
tolerance. DNA immunization appears to be substan-
tially less effective as aging progresses. In a rat
model, using orally administered adeno-associated
virus vaccine containing the NR1 subunit of the
NMDA receptor generated strong anti-epileptic and
neuroprotective effects. immunization, antibody,
biolistic transformation, viral vectors, library,
selectins, CTLA-4, T cell, gene therapy,
IL-2, monoclonal antibody, malaria, auto-
immune diseases, cancer, IFN, IL, immune
tolerance, polynucleotide vaccination, NMDA
receptor, adeno-associated virus, epilepsy, vac-
cine, surviving, carcinoembryonic antigen; Xu M
et al 2000 Trends Biotechn 18:167; Maloy KJ et al
2001 Proc Natl Acad Sci USA98:3299; Schadendorf D
2002 Semin Oncol 29:503; Chambers RS, Johnston SA
2003 Nature Biotechnol 21:1088, http://www.natx.
com/DNAVaccines.html; DNAvaccine design server:
http://miracle.igib.res.in/dynavac/.
Immunization, Intracellular: This is the same as
immunization genetic.
Immunization In Vitro: B lymphocytes are cultured in
vitro in the presence of cytokines and growth factor
complexes in order to produce antibodies. It has
somewhat limited significance; nevertheless, it may
be particularly useful when antibody production is
elicited against hazardous antigens. immunization
Immunoadsorbtion: Describes the process of binding a
cognate antibody to an antigen in order to facilitate
the separation of a specific type of antigen or antibody
from a mixture. In extracorporeal immunoadsorption
the blood is pumped out of the body and allowed to
react with an affinity column and then may be
pumped back into the body after this clearance, e.g.,
removal of radioactively labeled antibody. immu-
nofiltration
Immunoassay: This is based on the recognition of an
antigen by an antibody. radioimmunoassay, West-
ern blot, immunoblot, conformation-dependent
immunoassay
Immunoblotting: Refers to the separation of proteins by
gel electrophoresis and identification of an appropri-
ate component by the specific monoclonal antibody
labeled by fluorochrome or radioactivity. Western
blotting, electrophoresis
Immunocontraceptive: The vaccination of animals with
zonula pellucida proteins and adjuvants prevents
fertilization to a substantial extent. Immunization
with eppin is a reversible contraceptive measure used
in male primates. contraceptives; eppin; ORand
MG et al 2004 Science 306:1189.
Immunocytochemistry: Locates antigens in the cell with
the aid of labeled antibodies through microscopic
examination. immunolabeling
Immunodeficiency: This condition may be due to several
different (80) causes. Some of them have milder
effects whereas others are lethal. Immunodeficiency
is frequently caused by defects in the lymphocyte
differentiation system (thymus). Some of the immu-
nodeficiencies are parts of other syndromes such as
Downs syndrome, sickle-cell anemia, ataxia telangi-
ectasia, glycoprotein deficiency, glucose-6-phosphate
dehydrogenase deficiency, immunoglobulinimbalance
[deficiency of IgAand IgGbut increased IgM], defects
of the HLA histocompatibility system and some are
caused by non-genetic events, such as infection [HIV]
or drugs and various allergies that may have a genetic
component. Xq13.1-linked immunodeficiency with
hyperimmunoglobulin M (IgM) but absence of IgG,
IGA and IgE is caused by a defect in the interleukin
receptor IL-2Rc chain and interaction between CD40
and CD 40L and accounts for nearly half of all the
cases. As a consequence T cells and B cells do not
differentiate normally. The ICF syndrome (human
chromosome 20q11.2, immunodeficiency, centro-
mere instability [centromere areas 1, 9 and 16]) and
facial anomalies involve a defect in DNA methyl
transferase 3B. Methylation at specific sites in the
heterochromatin is essential for the maintenance of
chromosome integrity (Hansen RS et al 2000 Hum
Mol Genet 9:2575). Several immunodeficiencies are
the consequence of medical treatment, e.g., cancer
therapy or the use of immunosuppressive drugs
in tissue transplantation. Jak-3 deficiency causes
lymphocyte problems. ADA (adenosine deaminase)
recessive defects are responsible for about 1525%
cases of severe immunodeficiency. RAG1/RAG2
(recombination activating genes) interfere with the
generation of immunoglobulins and lead to impaired
lymphocyte receptors. Recessive mutation in ZAP 70
gene (2q12) is detrimental to the development of Tcell
receptors. Recessive mutations at 11q23 (CD3/
CD3) also cause immunodeficiency due to problems
with immunoglobulins. Mutations in the MHC class I
(6p21.3) and class II peptides adversely affect T and
B lymphocytes. agammaglobulinemia, hypo-
globulinemia, hypogammaglobulinemia, severe
Immunodeficiency 969
I
combined immunodeficiency [SCID], bare lym-
phocyte syndrome, Nezlof syndrome, DiGeorge
syndrome, chronic granulomatous disease, Dun-
can syndrome, Wiskott-Aldrich syndrome, Ep-
stein-Barr Virus, hyper-IgM syndrome, HLA,
CD40 ligand, RAG1/RAG2, ZAP-70, CD3,
ADA, RFX, methylation of DNA, lympho-
proliferative diseases, acquired immunodeficiency;
Fischer A 2004 Nature Immunol 5:23; http://bioinf.
uta.fi/idr/.
Immunodeficiency, Viral: acquired immunodeficiency
(AIDS)
Immunodominance: Of the many possible epitopes of
the antigen, cytotoxic lymphocytes (CTL) recognize
only one or a few. epitope; CTL; Brehm MA et al
2002 Nature Immunol 3:627.
Immunoediting: This proposes that tumors that evoke
strong immune response by Tcells develop a survival
mechanism by down regulating or eliminating the
molecules to which the immune system reacted.
immune tolerance, immunological surveillance
Immuno-Electronmicroscopy: Fluorescent antibodies
label cell constituents and thus the location of proteins
can be identified with electronmicroscopic resolu-
tion. histochemistry, microscopy; Yamazaki K,
Eyden BP 1998 J Submicroscopic Cytol Pathol
30:217.
Immunoelectrophoresis: This can be carried out by
different procedures. In diffusion, over the electro-
phoretically separated proteins, antisera (antibody or
antibodies) are placed in a trough. The protein bands
are permitted to diffuse in a radial manner from their
original posit-ion in the gel while the antibody
diffuses vertically and at their position of reaction
with each other an elliptical arc of precipitation is
formed. In rocket electrophoresis the antigen is
placed in the wells of the gel that contain the
antibody. After switching on the electric current the
antigen moves and forms a rocket-shaped trail of
precipitation as it reacts with the antibody. The length
of the rocket indicates the amount of antigen applied
to a well. ELISA, rocket electrophoresis
Immunofluorescence: Refers to the identification of a
protein (antigen) by direct adsorption to a specific
antibody that has an attached fluorochrome. Alterna-
tively, to the first (unlabeled) antibody a second
cognate, fluorochrome-labeled antibody is added for
the sake of immunostaining (indirect method).
fluorochromes, antigen, antibody
Immunogen: This is a substance which elicits an
immune response. immune system
Immunogenetics: This is concerned with the hereditary
and molecular aspects of antigen and antibody
systems and the immune response. http://imgt.cines.
fr:8104/home.html.
Immunoglobulins: These are the structural units of
antibody molecules. Each antibody is a heterotetra-
mer consisting of two identical light immunoglobulin
chains (either of two ) and two identical heavy
chains (see Fig. I10). The five heavy chains of
humans and mice exhibit considerable variations but
the light chains are fairly constant. There are five
classes (isotypes) of immunoglobulins IgM, IgG,
IgA, IgD and IgE, identified according to the heavy
chain subunits: , , , and The Ig heavy chains are
glycoproteins containing about 15, 4, 10, 18, 18%
sugars in a molecular mass of 70, 50, 55, 62 and 70
(kDa) for , , , , and , respectively. IgM is a
pentamer containing five heavy chains and five
light chains and one J chain; its molecular mass is
around 900 kDa.
Figure I10. The pentameric structure of immunoglob-
ulin M (IgM), joined by J chain in the center. Note the
absence of hinges. antibody
The J polypeptide (ca. 20-kDa), synthesized within
IgM secreting cells, is covalently attached between
two Fc domains antibody. and it is supposed to
initiate oligomerization. (The J polypeptide is not the
product of the J genes located between the variable
and constant gene clusters). The IgA antibody is a
monomer or a dimer or a trimer with molecular
weights 153, 325 and 580, respectively, and may have
a J chain. Besides the J polypeptide IgA may also
have a secretory component (SC) of 558 amino acids.
The SCis picked up by the secretory IgAdimers from
the surface of epithelial cells and it braces the IgA
dimers and protects them from proteolysis.
The SC is part of the transport receptor and
mediates the translocation of Ig and IgM into
glandular secretions. The IgG, IgD and IgE antibody
970 Immunodeficiency, Viral
I
monomers are of 150, 180 and 190-kDa, respectively.
IgD and IgE are of minor significance although the
latter mediates allergic reactions and its level is
elevated hundreds of fold in chronic infections. Each
of the five major types of heavy chains can be
associated with either one of the light chains.
The five classes of antibodies play somewhat
specialized roles. IgG is the humoral, circulating
antibody and it is the major class. It can cross the
placenta and enter extravascular areas. IgE manages
the allergic reactions and IgA has a major role in
defense against microbial infections. IgM and IgA
have two subclasses, IgG and the chains have four,
designated as e.g., IgM1 and IgM2. Some of the IgG
subclasses can cross the placenta. IgM is secreted
in low amounts by B lymphocytes but this is the
first immunoglobulin produced by newborns which
readily activates the complement cascade, and thus
represents one of the first lines of defense. IgA is
produced mainly in the gastrointestinal system and
plays a major role in mucosal immunity. Within these
subclasses allotypes are distinguished, 25 for human
IgG, 2 for IgA and 3 for the kappa () chain. These
allotypes represent antigenic markers on the immu-
noglobulin chains and are designated as e.g., Gm1,
Gm2 Am1Km1 for IgG, IgA and chain
markers, respectively. The allotype variants represent
amino acid substitutions at one or more sites. The
characteristic series of allotype markers are inherited
as gene blocs and are called haplotypes.
The genes encoding immunoglobulins are clus-
tered in three supergene families. The heavy chain
genes are clustered at human chromosomal location
14q32.33. The genes are in human chromosome
2p12, whereas the gene family is in human
chromosome 22q11.12.
Within the approximately 7,000-kb heavy chain
region in the long arm of chromosome 14 the genes
L encode the signal that leads the polypeptide to
the endoplasmic reticulum. V
H
(variable heavy), D
(diversity), J (juncture) and the various constant heavy
chain genes C

to C

, are arranged in groups. The


groups are separated by long base sequences (

) and
spacers () with switch signals (S) in front of the
constant heavychaingenes. Thegeneral organizationof
immunoglobulin genes is very similar in all mammals
although they are located in different chromosomes:
(indicates pseudogenes). Up front of this sequence,
the basal promoter of the Ig heavy chains contains non-
translated regulatory transcriptional elements, such as
the dispensable heptamer consensus: (5-CTCATGA-
3) and 10 to 40 bp downstream the indispensable
octamer consensus: (5-ATGCAAAT-3). The latter is
30 to 60 bp upstream from the TATA box, that is
followed within about 20 to 30 bp the transcriptional
initiation site for the LVDJ and the constant heavy
chain sequences, to
2
. (The orientation of the
octamer is opposite to the direction of transcription).
Between the LVDJ region and the constant heavy
chain genes, there are enhancer elements of the
5-CAGGTGGC-3 motif and three core repeats of
multiple GC sequences.
The cluster is similarly organized in human
chromosome 2:
5
0
LV
S
V
n
JJJJJ
1 constant gene group3
0
The genes are in human chromosome 22. The
variable genes occur in six groups. Here the J genes
are not clustered separately but situated in front of the
six constant gene groups. Some of the genes are
outside the clusters and may not be functional. The
individual segments are quite variable in size. The
V
S
, one of the switching sequences, is explained here.
The base promoter of the light chain contains at
about 100 bp upstreamfromthe transcription initiation
site a pentanucleotide consensus, and within 90 to
60 bp the octamer consensus (oriented in the direction
of the transcription) follows. This does not have the
heptamer shownat the heavygenes. The TATAboxis at
about the same distance fromthe transcriptioninitiation
site as in the heavy chains. There are enhancer
elements, designated as B (5-GGAAAGTCCCC-3)
and E1 to E3 (variants of the enhancer motif shown
at the heavy chains), between the LVJ genes and the
constant gene group. The strongest enhancer is the
B. Both the heavy and light gene enhancers act
preferentially in B lymphocytes. The heavy chain
enhancers seem to be constitutive whereas the light
gene enhancers become active after the rearrangement
of the genes. Besides the enhancers, the immunoglobu-
lin genes appear to have silencers of expression for non-
lymphocyte chromosomes. Turning on the promoters
requires transcription factors, one of them is 60-kDa
OTF-2 which has specificity for the immunoglobulin
enhancer consensus 5-CAGGTGGC-3. The 90-kDA
OTF-1a general mammalian transcription factor is also
present in the lymphocytes. The DNA-binding domains
of these two factors are very similar but their other
domains are different. These enhancers also bind other
types of proteins and the only lymphocyte-specific
enhancer appears to be the octamer. The light chain
specific transcription factor is protein NF-B that binds
to the 5-GGGPu(C/T)TPyPy(C/T)C-3 motif. After the
immunoglobulin light chain has undergone rearrange-
ment, preparatory to transcription, the pattern of the
nuclease-sensitive sites in the promoter region is
altered.
5LV
n
V
1
D
1
D
20
JJJJ


3

1


2

4

2
3
Immunoglobulins 971
I
The variable-diversity regions of the light and
heavy chains determine the antibody specificity. The
antigen has to fit, be complementary to the NH
2
end
of the antibody. The three complementarity deter-
mining regions (CDR1, CDR2 and CDR3) represent
the hypervariable region of the antibody (that has the
highest specificity for the antigen).
Although in the germ line the complete array of all
immunoglobulin genes is present, during develop-
ment various rearrangements and elimination of
genes take place. Thus, the mRNA does not represent
all the genes all the time in the somatic cells but
different ones may be represented, depending on their
transcription, stimulated as the immune response
unfolds. The heavy chain genes can generate an
enormous variety of polypeptides. The variable
region is put together from a menu of hundreds of
V
H
, about 20 diversity (D) segments and 5 or more
joining segments (J
H
). The V, J and constant heavy
gene clusters are separated by sequences containing
12 or 23 spacers, flanked by conserved heptamer
(7mer) and nonamer (9mer) nucleotide tracts that serve
the purpose of rearrangements. The general organiza-
tion of the switching sequences is diagrammed here.
The heavy chain genes are in mouse chromosome 12
and the corresponding human gene cluster is in
chromosome 14. The light genes of the mouse are
in chromosome 6 whereas the homologous human
genes are in chromosome 2. The chain genes are in
mouse chromosome 16 and in human chromosome 22.
The 12 and 23 bp spacers are shown in bold numbers
Recombination is limited to 12 and 23 base spacers
(12/23 rule). The RAG(recombination activating) gene
products provide signals for the recombinational signal
sequences (RSS) for double-strand breaks. The 12/23
and the RAG signals are concerted and mutation in one
signal prevents cleavage at both. The blunt signal ends
andthe codingends thenforma hairpin-like structure by
transesterification with the assistance of a score of repair
enzymes. The hairpinintermediates leadtothe assembly
of the antigen receptor sequences of the genes. This
process has similarities to retroviral integration.
The switching recognition sites in the two mouse
light chain gene series are as follows:
The consensus sequences shown here are present in
between each of the variable and joining genes in the
clusters. Thus, rearrangements alone can generate
enormous variability, parti-cularly within the heavy
and clusters each of which has hundreds of variable
region genes.
Since the cluster has only a very small number of
variability genes, its own contribution to the antibody
arrays is minimal, but in combination with the highly
variable heavy chains it may produce about 100,000
different antibodies. The heavy chain assemblies
are capable of generating more than a million types of
antibodies. This assembly process is limited to the
lymphoid cells. The T cell receptor assembly occurs
only in the Tcells and the complete assembly of the Ig
genes takes place in the B cells. The accessibility of
the V(J)Drecombinase to the complementarity region
is regulated by the transcription system. The enhancer
motif called E-box E3 and other upstreamregulatory
elements alsocontrol accessibility of the recombinase.
The V and J consensus sequences show the
opposite orientation.
The opposite orientation means that the same
nonamer (9MER) can be either:
ACAAAAACC
TGTTTTTGG
or
GGTTTTTGT
CCAAAAACA
in the DNA double-
strands as the sequences are inverted horizontally and
vertically (). The types of sequences shown insure
that V genes and J genes do not recombine within the
V or J group but V genes recombine with J genes
because one type of spacing can recombine only with
another type of spacing. Also, in the heavy gene
cluster a V gene is obligated to transpose to a D gene
and that in turn can be relocated to a J gene. The V
gene and the J gene have the same type of spacers
(different from the D gene) thus the relocation of a V
gene to a J gene must involve a D gene. These types
of relocation mechanisms are frequently called
recombination and a recombinase system. One must
keep in mind that these events are not crossing overs.
The 12 and 23 base spacers apparently represent one
or two turns, respectively, of the DNA double helix
and thus indicate the mechanics of the rejoining. The
V and J genes can also recombine by a breakage -
reunion mechanism that may take place at the
972 Immunoglobulins
I
heptamers (7mers) at the ends of the two coding units
and this leads to the elimination of the interjacent
segment with the signal ends. The ends of the coding
sequences are the coding ends. The signal ends may
be joined to form a circular DNA structure and this
circularization, followed by elimination, is apparently
a major source of rearrangements. In some instances
there is an inversion of the V gene relative to the J
gene. In such a case the intervening material may not
be deleted although the V gene may be inactivated.
Some of the rearrangements are non-productive
because they occur at random and are in the wrong
register. Since codons are triplets, two-thirds of the
rearrangements may result in garbled sequences.
Some nucleotides may be lost at the coding ends and
some may be added (N nucleotides) by the enzyme
deoxynucleotidyl transferase. At the coding ends, the
5 terminus of one of the DNAstrands may covalently
fuse with the 3 terminus of its complementary strand.
When the resulting hairpin structure breaks, a
protruding end of nucleotides may be formed that can
serve as a template to generate an inverted terminal
repeat of a few nucleotides (P nucleotides). The 96th
codon at the endof the V
H
gene is actually generated by
a fusion between the V and J genes. This is a critical
point because the 96th amino acid is part of the antigen-
bindingregion as well as the connection of the light and
heavy chains. Both deletions and additions increase the
variability of the antibody genes. The V
H
regions can
combine with any of the five constant heavy chains (,
, , , and their subclasses, isotypes) and this is a
source of another variation.
The expression of the immunoglobulin genes
requires that the promoter be transposed to the vicinity
of an enhancer base promoter structure. The enhancer
becomes normally active only in the B lymphocytes.
Before any antigen is encountered, IgMand IgDclass
antibody production starts. In such virgin Bcells, both
immunoglobulins have identical variable regions but
they may differ in the constant regions of the and the
chains. Since Bcells are diploid, genes in only one of
the two homologous chromosomes can be expressed
at a time and only one type of rearrangement can
function in a cell, this is known as allelic exclusion.
The virgin B cells can then differentiate either into
plasma cells or into memory cells upon exposure to an
antigen. The former become an immediate producer
of an antibody, the latter would be activated into
plasma cells only upon subsequent exposure to the
same antigen. The differentiation is aided by
lymphokines (a variety of growth regulating proteins),
and various T lymphocytes (T
H
, T
S
) and macro-
phages. The association of the virgin lymphocytes
with an antigen triggers the mechanism of isotype
switching. Isotype switching brings about the selec-
tion of the proper heavy chain constant region by a
process of transcription although DNA deletions may
also be involved. In the undifferentiated B lympho-
cyte transcription begins at the heavy chain gene
leader sequence upstream and continues through the
variable and diversity regions to the end of the gene,
passing through exons and introns. Polyadenylation
signal follows the last exon of the transcribed
constant region of the and genes:
Two types of chains exist at the early stage of the B
lymphocyte. The
m
chain (with a hydrophobic C
terminus and an alternative processing event) and .
The former is included in the lymphocyte membrane as
a monomeric Igmantibody (2 light-2 chains) whereas
the secreted IgM becomes pentameric and also
adopts a ca. 20 kDa J peptide with the composition of
(
2

2
)
5
J (the J is synthesized in the B lymphocyte but
not coded in the constant heavy chain cluster). After
recombination and deletionoccur at one of the Sswitch
points, in the non-coding ca. 2-kb upstream tracts, at
the (GAGCT)nGGGGT motifs, of the constant heavy
chain genes, the rearranged gene are transcribed. The
introns are eliminated and the transcript is processed
into polyadenylated mRNA. The mRNA is translated
into the individual heavy chain monomers:
V
2
---D
5
-J
5
---- PRIMARY TRANSCRIPT
IgG 50 kDA polypeptide

switching at
V
2
---D
5
-J
5
---- PRIMARY TRANSCRIPT
IgA 55 kDa polypeptide

switching at
In the examples given here the same VD and J
genes are shown, actually any of the VDJ genes can
be selected before switching. Additional variation is
5
0
Promoter-Enhancers--V
n
V
1
---D
20
D
1
-J
n
J
1
--S---S--S---S-S- 3
0
DNA
virgin B cell V
2
---D
5
-J
5
--------- PRIMARY RNA TRANSCRIPTS
processing V
2
D
5
J
5
polyA andV
2
D
5
polyA two mRNAS
translation V
2
D
5
J
5
and IgM and IgD POLYPEPTIDES
Immunoglobulins 973
I
generated by somatic mutation during the prolifera-
tion of the lymphocyte clones. The frequency of these
mutational events (about 10
3
per base) appears to be
higher than the usual mutation rate of other types of
genes. After the heavy chain is completed it may
combine with any of the two light chain polypeptides.
IgG and IgA are further polymerized to form the final
antibody. The activity of B cells is terminated partly
by binding the antigen to the secreted antibody. This
prevents the binding of the antigens to the B lympho-
cyte receptors and thus the stimulation of immuno-
globulin synthesis ceases. Some birds (ducks, geese,
swans) produce immunoglobulin Y (IgY), which
does not occur in mammals or in some other avian
species but it bears similarities to IgG and IgE. IgYis
produced in larger and smaller forms; the latter is
deficient in the crystalline fragment.
The completed polypetide chains are modified
glycosylation (using covalently D-galactose, N-
acetyl-D-galactosamine, N-acetyl-D-glucosamine,
L-fucose, D-mannose and acetylneuraminic acid)
that affects their structure and function. IgG has only
3% carbohydrates whereas other chains may have
34 times as much. The glycans are mainly at the
constant regions of the heavy chains although the
number and location of the glycosylation sites vary.
Glycosylationaffects the activationof the complement,
their stability in relation to proteolysis, the number of
antigen binding sites available (avidity), etc. In certain
diseases (rheumatoid arthritis, tuberculosis, Crohns
disease, Sjgren syndrome, scleroderma and some
autoimmune conditions) the IgG molecules lose their
galactose. The agalactosyl IgG molecules decrease
during pregnancy and their level is lower during the
first 25 years of life thereafter it increases again.
In humans and pigs the proportion of : chains is
about 6:4 whereas in rodents chains are about 19
times more common than the chains. Chickens have
only light chains, and in many other animals
(bovines, horses) the chain is preponderant. All
vertebrates synthesize immunoglobulins yet the
antibodies of the lower animals (fishes, amphibians,
reptiles, birds) are somewhat different from those of
higher forms. In mammals usually five types of
immunoglobulins are produced. There are excep-
tions, however. Rabbits lack IgD while mice and rats
have all five types. In cattle, sheep, pigs and horses
IgM, IgG, IgA and IgE occur. In cats IgG, IgM,
IgA and IgE and several subclasses are found
while dogs have all five types. In camels and llamas
the IgG molecules are built of heavy and light chains
whereas other immunoglobulins have only heavy
chains and the variable domain of the light chain
is missing. Transgenic mice containing camelid
heavy chain antibody (HCab) loci rearrange properly,
result in allelic exclusion, efficiently rescue B cell
development, and undergo class switch recombina-
tion and affinity maturation. They generate func-
tional HCAbs subsequent to antigenic challenge,
providing a new way of producing human HCAb
when the llama variable heavy chain (VHH) regions
are replaced with soluble human VH (Janssens R et al
2006 Proc Natl Acad Sci USA 103:15130).
In invertebrates there are some immune defense
molecules. In the Drosophila, the Amalgam (ama, 1
47.5) encoded cell adhesion proteins display some bear
immunoglobulin-like domains. The fasciclin II glyco-
proteins involved in neuronal recognition of grass-
hoppers have five immunoglobulin-like domains. It is
conceivable that the PapDprokaryotic protein involved
in pilus assembly has some evolutionary relation to
immunoglobulins. The similarity is not in the amino
acidsequencebut inthe overall structure of the domains.
Extremely large phage antibody libraries can be
generated in bacteria with the aid of two non-
homologous Lox sites in a phagemid vector. The
exchange among variable heavy and variable light
chain genes creates functional recombinants with a
diversity of 3 10
11
. Gene conversion generates
additional diversity. antibody, surrogate chains,
IgNAR, immune system, immunization, lym-
phocytes, complement, HLA, TCR, T cell,
T cell receptors, B cell, DNA-PK, RAG,
RSS, V(J)D recombinase, antibody gene
switching, class switching, AID, SCID, ter-
minal nucleotidyl transferase, repertoire shift,
affinity maturation, CDR, somatic hypermuta-
tion, hypermutation, accessibility, translin,
monoclonal antibody, hybridoma, multiple
myeloma, macroglobulinemia, ELISA, tail-
piece secretory, membrane segment, transposons
[Tn3, Tn5, Tn7, Tn10], hemolin, named
diseases under separate entries, Cre/LoxP; Bross
L et al 2000 Immunity 13:589; Arakawa H et al 2002
Science 295:1301; immunoglobulin diversification
paths: Maizels N 2005 Annu Rev Genet 39:23;
immunoglobulins and T cell receptors: http://imgt.
cines.fr; variable genes: http://www.vbase2.org/.
Immunoglobulins in the Human Serum: (mg/mL), IgG1,
146 kDa [1]: 9; IgG2, 146 kDa [2]: 3; IgG3,
170 kDa [3]: 1; IgG4, 146 kDa [4]: 0.5, IgM,
970 kDa []: 1.5; IgA1, 160 kDa [1]: 3, IgA2,
160 [2]: 0.5; IgD, 200 []: 0.03; IgE, 200 kDa
[]: 0.0001. Immunoglobulins also occur in milk,
tears, genitourinary and lung secretions.
Immunohistochemistry: immunocytochemistry
Immunolabeling: immunostaining, ELISA, im-
munofluorescence, RIA, immuno-scintography,
monoclonal antibody, immunocytochemistry,
immunosensor, fluorochromes
974 Immunoglobulins in the Human Serum
I
Immuno-Liposome: Refers to a liposome that is coated
with target-specific antibodies to deliver, e.g.,
therapeutic agents to cancer cells. cancer gene
therapy, liposome, bispecific antibody
Immunological Learning: The quality of the antibody
improves as clonal selection progresses. clonal
selection
Immunological Memory: Survivors of a cell (individual)
that mounted an immune response are more
effectively protected in the event of a subsequent
infection. The mechanism of this protection may be
based on the maintenance of specific Tor Bcells even
in the absence of the antigen or some types of
lymphocytes have the ability to remember the
antigen. Recurrent low levels of infection may
maintain some lymophocytes or some regulatory
networks of cytokines respond in case of subsequent
infection. immune system, lymphocytes, Tcell,
B cells; Utzny C, Burroughs NJ 2001 J Theor Biol
211:393; HU H et al 2001 Nature Immunol 2:705.
Immunological Privilege: At some tissue sites (such as
the central nervous system, maternalfetal interface,
adrenal cortex, testis, ovary, hair follicles, liver) the
immunological reaction is not elicited either by
acquiring tolerance or by failure of the antigens to
communicate effectively with the other sites.
Immunological Surveillance: This is one of the defense
mechanisms against cancerous body cells. The
surface antigens of the transformed (cancer) cells
are different from their normal counterparts. The
immune system continuously monitors the body for
invading microorganisms and other foreign antigenic
material (macromolecules, grafts, etc.) and also
recognizes the cancer cells at an incipient stage and
with the aid of the immune system (Rousseau Merck
MF et al 1996 J Exp Med 183:725) gets rid of them.
Experimental data in support of this idea indicated
that antibodies produced against mammary cancer
preferentially recognized the metastatic cells without
reacting with the normal cells. The CCR7 chemokine
receptor is an organizer of the immune response (see
Fig. I11). Cancerous transformation may be initiated
by a single mutation although for the development of
neoplasias additional events are required. Mutation
rates per cell are in the range of 10
9
, because the
human body may have 4 to 5 times more cells, cancer
mutations may affect each person numerous times
during his lifetime. Nevertheless, the incidence of
death due to cancer is about 0.2 of all deaths. If no
biological protection was available, all individuals
would have had cancerous transformation(s). The
general validity of immunological surveillance for
protection against cancer has been questioned
because several types of cancers occurred at the
same frequency in immune-compromised or geneti-
cally weak immune system animals as in normal
individuals. In a nude mouse with a defective immune
system the incidence of cancer did not increase.
When naive CD4
+
T cells specific for an antigen
expressed by tumor cells were transferred into tumor-
bearing mice transient clonal expansion occurred
early after transfer, accompanied by phenotypic
changes associated with antigen recognition
(Stavely-OCarroll K et al Proc 1998 Natl Acad Sci
USA 95:1178). In recent years immunosurveillance
has attracted renewed attention (Dunn GP et al 2004
Immunity 21:137).
Figure I11. The small lymphocyte (L) is attacking a
large tumor cell (T). As the cancer cell begins to lyse,
first the microvilli dilate, then surface vesicles (V)
appear and eventually it shows blebbing before
destruction. (Courtesy of Dr. A. Lepins. See also
Lepins A et al 1978 Cell Immunol 36:331)
In transgenic mice where T lymphocytes and
tumor-associated antigens could be monitored in
some tumors a degree of immune tolerance devel-
oped. Recent information (Ochsenbein AF et al 2001
Nature [Lond] 411:10558) has revealed that (i)
tumor-specific induction of protective cytotoxic T
cells (CTLs) is contingent on how many tumor cells
reach the secondary lymphatic organs early and stay
there long enough; (ii) diffusely invading systemic
tumors can eliminate CTLs; (iii) tumor cells which
are either located outside the lymphatic organs or are
not within the reach of T cells stay on; and (iv) the
major histocompatibility class I molecules may not be
protective. Killer cells, CD8
+
T cells and activated
macrophages express the stimulatory NKG2D lectin-
like receptors and this may also contribute to the
rejection of tumor cells.
In BALB/c mouse ascites-injected animals may
exhibit complete resistance to different types of
cancer determined by a dominant factor. Advanced
cancer cells are destroyed by innate leukocytes
without damaging the normal cells (Cui Z et al
Immunological Surveillance 975
I
2003 Proc Natl Acad Sci USA 100:6682). immune
system, cancer, chromosome breakage, genetic
tumors, cancer prevention, CCR, cancer thera-
py, T cell, MHC, tumor suppressor factors;
Diefenbach A et al 2001 Nature [Lond] 413: 165;
Shastri N et al 2002 Annu Rev Immunol 20:463;
Dunn GP et al 2002 Nature Immunol 3:991.
Immunological Synapse: Refers to the TCRengagement
with the antigen-presenting cells with the aid of
integrin family adhesion molecules. TCR, anti-
gen-presenting cell, integrin
Immunological Tests: These tests are extremely sensi-
tive for the detection of the presence of a particular
protein or other molecules, which can form cross-
reacting material (crm) with specific antibodies.
Frequently, if the quantity of the material is very
low and standard biochemical assays are not sensitive
enough for identification, immunoprobes are used
for testing. antibody preparation, immunoprobe,
immunoscreening, immunofluorescence, path-
ogen identification
Immunological Tolerance: immune system
Immunomicelles: These are polyethylene glycol
phosphatidylethanolamine conjugate tumor targeting
vehicles for the delivery of poorly soluble drugs (e.g.,
taxol). To the micelle mouse an anti-tumor antibody
(mAb2C5) is attached for specific recognition of the
target. liposome; Torchilin VP et al 2003 Proc Natl
Acad Sci USA 100:6039.
Immunomodulators: Refers to viral encoded proteins
regulating antigen presentation, regulators of cyto-
kines, cytokine antagonists, inhibitors of apoptosis
and interfering with the functions of the complement.
antigen-presenting cell, cytokines, apoptosis,
complement
Immunopanning: This is a cell separation technique
used in neurobiology. (Gard AL et al 1993 Neuro-
protocols 2:209).
Immuno-PCR: This is a polymerase chain reaction
version resembling Capture-PCR. It detects specific
antibody-DNA conjugates with high sensitivity.
Capture-PCR, polymerase chain reaction; Sano T
et al 1992 Science 258:120.
Immunophilins: These two classes of proteins bind
immunosuppressants such as either rapamycin and
FK506 (FKBP) or cyclosporin. All known immuno-
philins display rotamase (peptidyl-prolyl cis-trans
isomerase) activity in vitro. The 59-kDa member of
the FKBP family is a component of the inactive
glucocorticoid receptor. Immunophilins apparently
interact with protein kinases of the signal trans-
ducting paths and with the heatshock protein 90,
a chaperone. Immunophilins FKBP12 bind to the
GSGS domain of the TGF receptors and stabilize
them in an inactive form. Activation occurs upon
phosphorylation. The implantation of blastocysts into
the uterus requires estrogen and progesterin and
immunophilin FKBP52 serves as a co-chaperone
for the steroid nuclear receptors in this process
(Daikoku T et al 2005 Proc Natl Acad Sci USA
102:14326). FK506, cyclosporin, rapamycin,
cyclophilin, T cell, immunosuppressants, es-
trogen, progesterin, implantationnuclear receptors,
photosystems; Ivery MT 2000 Med Res Rev 20:452.
Immunopolymorphism: Denotes variation in T cell
receptors, major histocompatibility system and anti-
gens. http://www.ebi.ac.uk/ipd/.
Immunoprecipitation: The reaction of an antigen with a
cognate antibody may lead to blood coagulation or to
the selective precipitation of a protein. From a
mixture of proteins the interactive molecules (en-
zyme-substrate, proteins of signaling pathways, etc.)
may be co-precipitated. Chromatin immunoprecipita-
tion (ChIP) can identify the protein components of the
transcriptional machinery (Zhou Q-P et al 2004
Nucleic Acids Res 32:884). Co-immunoprecipitation
occurs when two cross-reactive molecules are
isolated together. affinity chromatography, ChIP,
ChIP-chip, chromatin transcription factor immuno-
precipitation detection method: http://chip.dfci.
harvard.edu/wli/MAT, Western blotting, micro-
calorimetry, gel retardation assay, protein com-
plexes, pull-down assay, paired-end ditag
Immunoprobe: This is also known as immunoblot.
Bacterial colonies are immobilized on a filter and a
specific antibody is added. This antibody can bind the
epitope of a second antibody or an antibody plus
protein Athat may be labeled by a radioactive isotope
(I
135
) or a biotinylated molecule. The complex can
then be detected by autoradiography on the dot blot or
separated in SDS-polyacrylamide gel and the labeling
identifies the substance of interest. Western blot-
ting, colony hybridization, protein A, probe,
DNA probe
Immunoproliferative Disease, X-Linked: Epstein-Barr
Virus
Immunoprophylaxis: Refers to the use of vaccines or
antisera for the prevention of infection (disease).
Immunoproteasomes: These are used for degradation of
foreign antigens by cytotoxic Tcells. The proteins are
ubiquitinylated and partially degraded by immuno-
proteasomes. In these proteasomes some of the
subunits of the constitutive proteasomes are replaced
by other polypeptides induced via interferon
(IFN). Thus, immunoproteasomes are different from
976 Immunological Synapse
I
the constitutive ones in structure and also in stability
because after the disappearance of the foreign
antigens and IFN the cells return to the constitutive
state. This cytokine also induces the proteasome
activator PA29, which facilitates antigen presentation
through a more open proteasome structure. IFN
induces the formation of proteasome maturation
protein (POMP) and the proteasomal 5i subunit
low-molecular weight protein 7 (LMP7) and 2i
multicatalytic endopeptidase-like 1 protein (MECL1).
These subunits replace the constitutive proteasome
homologs 1, 2 and 5. LMP7 activation leads to
degradation of POMP and a decrease of proteasome
activity, reduction of the MHC class I surface
expression and induction of apoptosis (Heink S et al
2005 Proc Natl AcadSci USA 102:9241). Immuno-
proteasomes have a strong influence on the repertoire
of T cells in antigen-specific immune response
(Osterloh P et al 2006 Proc Natl Acad Sci USA
103:5042). T cells, antigen processing and pre-
sentation, proteasome, interferon; Kloetzel P-M
2001 Nature Rev Mol Cell Biol 2:179.
Immunoscintigraphy: By using a scintillation camera
(capable of detecting the flashes emitted by radioac-
tive isotopes) radioactively labeled monoclonal
antibodies can be localized in the body or tissues by
even a three-dimensional image.
Immunoscreening: The product of a gene is identified
on the basis of a cognate antibody.
Immunosensor: This is a solid-state apparatus capable
of detecting antigen-antibody binding, based on
changes in mass or electrochemical or optical
properties. It may be employed in clinical, environ-
mental or food analysis.
Immunostaining: Purified antibodies can be labeled
by fluorochromes and their specific recognition sites
can be visualized in situ with the aid of fluorescence
light microscopy. Also, antibodies labeled by colloidal
gold permits their analysis by electronmicroscopy.
Immunostimulatory DNA (ISS): This contains within
short stretches of plasmid vehicles CpG dinucleo-
tides: 5GACGTC-3, 5-AGCGCT-3 or 5AACG%
%-3. Such sequences promote the production of
interferon- and - and interleukin-12. The signifi-
cance of this finding for gene replacement therapy is
that ISS may cause the production of proinflamma-
tory cytokines and thereby down regulate gene
expression. Immunostimulatorygene expressionboosts
immunological surveillance and also facilitates cancer
therapy. It may be achieved by the use of IL-2, with a
tumor-specific antigen, or an anti-erbB-2 single chain
antibody. therapy, cytokines, T cells, erbB,
single-chain Fv fragment, cancer gene therapy;
Uchijima M et al 2001 Biochem Biophys Res
Commun 286:688.
Immunosuppressant: Blocks or reduces the immune
response by irradiation, specific antimetabolites or
specific antibodies. cyclosporin, cannabinoids,
calcineurin, immunophilins
Immunosuppression: The activation of the immune
system generally involves the activation of cytokines
and cell adhesion. In tumor cells the immune system
is suppressed and this suppression is suspected to
involve the inhibition of lymphocytes (CTL, NK, B
cells) by IL-2, IL-10, TGF-, etc. Repression of this
process calls for the inhibition of the transcription
factors required to develop the key elements of the
immune system (see Fig. I12). Glucocorticoids,
prednisone (also a glucocorticoid), the fungal cyclic
oligopeptides, e.g., cyclosporin, mycophenolic acid
(C
17
H
20
O
6
), acidcyclophosphamide (carcinogen),
azathioprine (an arthritis drug), cytarabin (cytosine
analog), mercaptopurine (a purine analog), metho-
trexate (a folic acid antagonist), muromonab-CD3
(a murine monoclonal antibody [IgG
2
] targeted to
the lymphocyte membranes), etc. are used. The new
suppressants may prevent stimulation of the T cell
receptors (TCR) or the co-stimulatory responses or
down regulate the amplification of the specific
antigen-responding T cells.
Specific Janus kinase-3 inhibitors (CP-352.664,
CP-690.550) may also prevent allograft rejection.
Janus kinase signals to several cytokines (Changelian
PS et al 2003 Science 302:875). glucocorticoids,
cyclosporin, cyclophosphamide, methotrexate,
immune tolerance, immune system, hyperacute
reaction, Gal1-3Gal, IL-2, IL-10, TGF,
CTL, killer cell, Jak kinase, transplantation
in utero; Kahan BD, Koch SM 2001 Curr Opin Crit
Care 7(4):242.
N
N
N
CP-352,664 CP-690,550
N
H
N
N
N
N
N
N
O
H
Figure I12. Immunosuppressor molecules
Immunotherapy: This includes immunization, the use of
immunopotentiators, immunosuppressants, hyposen-
sitization to allergens, monoclonal antibodies and
transplantation of bone marrow or thymus. In rats
heatshock proteins prepared from the same cancer
(but not from others) retarded the progression of the
primary cancer, reduced metastasis and prolonged
Immunotherapy 977
I
life. Another possibility is to fuse antigen-presenting
dendritic cells with carcinoma cells and the cell
hybrids are used for immunization of syngeneic
animals. When surgically removed cancer cells
(surface antigens) were delivered to the same animal
the mouse body immuno- rejected the cancer. In some
instances both CD4
+
and CD8
+
T cells responded
favorably and the primary tumors as well as the
metastatic cells were rejected. Immunotherapy of
cancer may use IL-2, IL-4, IL-5, IL-6, IL-1 receptor
antagonists, interferon, tumor necrosis factor (TNF),
granulocyte-macrophage colony stimulating factor
(GM-CSF) or interferon (IFN) to boost the host
effectors and the MHC class I and II molecules or
apply tumor-specific antigens in order to activate
cytotoxic T cells against the cancer cells. GM-CSF
appears to be particularly effective. When it is
difficult for the antibody to access sensitive tissues
in the tumor, a novel approach is to target the blood
vessel internal epithelium with the immunoglobulins
through intravenous injection (Oh P et al 2004 Nature
[Lond] 429:629). In humans TNF (tumor necrosis
factor) and
4

1
integrin are the most successful
targets for the treatment of several autoimmune
diseases. mentioned concepts as separate entries,
bacillus Calmette-Guerin, vaccinia virus, SER-
EX, statins, cancer gene therapy, adoptive
cellular therapy, autoimmune diseases, planti-
body; Chen ZN et al 2001 Cell Biol Int 25:1013;
McLaughlin PM et al 2001 Crit Rev Oncol Hematol
40:53; Blattman JN, Greenberg PD 2004 Science
305:200.
Immunotherapy, Active Specific: This therapy boosts
the immunogenic response by immunization with
endogenous antigenic determinants of the cells. This
is expected to result in immunological memory and
thus have a long-lasting effect. immune response,
memory immunological; Pol S et al 2001 J Hepatol
34:917.
Immunotherapy, Adoptive (passive): Ex vivo-selected
allogeneic transgenic donor lymphocytes are em-
ployed against viral infection or leukemia. After
reintroduction it may become necessary to select
against the introduced lymphocytes in case host
graft incompatibility occurs. The negative selection
requires the activation of a special suicide gene.
ex vivo, allogeneic, leukemia, suicide vector;
Bathe OF et al 2001 J Immunol 167:4511.
Immunotherapy, Passive: If a patient does not have an
active immune system, preformed specific antibodies
may be employed.
Immunotoxin: This may be an antitoxin or a specific
antibody equipped with a bacterial, fungal or plant
toxin. The monoclonal antibody (Fab domains, Fv)
provides the means of homing on the special target
cell(s) of cancer (lymphoma, melanoma, breast and
colorectal carcinomas) or graft rejection (bone
marrow transplant) or T cells responsible for autoim-
mune disease (arthritis, lupus or HIVinfected Tcells).
In addition it may carry cytokine and soluble
receptors to assist targeting. The toxin (Pseudomonas
exotoxin, diphteria toxin, ricin, abrin, -sarcin)
then specifically destroys the target by inhibiting
local protein synthesis without affecting the other
cells. Lysosome targeting (lysosomotropic) amines
(NH
4
Cl), chloroquine and carboxylic ionophores
(monesin) protect the cells from some immunotoxins
(e.g., diphteria toxin) but make them more sensitive
to others (e.g., ricin). The clinical applicability of this
therapy is still very limited. The toxins may damage
to some extent other cell types too. magic bullet,
antitoxin, monoclonal antibody, antibody engi-
neering; Knechtle SJ 2001 Philos Trans R Soc Lond
BBiol Sci 356:681; Manzke Oet al 2001 Med Pediatr
Oncol 36:185.
Impact Factor: This is a scientometric index monitoring
the citation frequency of average articles in
particular journals within a specific period of time
(Garfield E. 1972 Science 178:471). It is calculated
by dividing the number of cited articles in a journal by
the number of articles published in that journal during
a period of two years. The information is available in
the Journal Citation Reports (Science Citation Index)
in alphabetical order and by grouped fields. It is
commonly used for the evaluation of the performance
of individuals or departments because it indicates the
impact of the publications. It is a useful tool of
evaluation within a discipline although papers
describing methods are cited more frequently than
those dealing with data and theory. It is not entirely
suitable for comparison across different disciplines
because glamorous journals are commonly cited
more frequently than the traditional ones. The
Institute of Scientific Information carrying out the
tallying may also be affected by some human errors
(Nature [Lond] 2002 vol. 415:101, ibid. 726, ibid.
731). Nevertheless, it is probably the most objective
tool for rating the prestige of a journal. The Citation
Index is also used to assess the impact of the authors
of the scientific papers. Another proposed factor for
the evaluation of scientific output is the h index,
which considers the number of papers with higher
h value and ignores those which are below; i.e. it
considers the number of publications that received a
certain number of citations. For example, eight
978 Immunotherapy, Active Specific
I
journal research papers of the author of this book
received (995) an average of 124 citations since his
retirement. It was suggested that such an index
permitted realistic comparisons across scientific
disciplines (Hirsch JE 2005 Proc Natl Acad Sci
USA 102:16569). The latter approach has obvious
merits relative to counting only the number of
publications irrespective of their impact that may
yield only a trash index. Obviously large numbers of
publications which are not useful to the scientific
community are definitely harmful because the reader
may not be able to judge their merit before reading
them and wastes his valuable time that could be spent
on meritorious publications. There are increasing
problems, however, in determining the number of
citations because there are too many scientists with
the same name. Also, older papers even if they
continue to be very useful may not be included in the
bibliographies just because of the date of publication.
Mendels Versuche paper is rarely cited today and
Watson and Cricks epoch-making 1953 paper in
Nature is infrequently mentioned in current research
publications. Books and review papers may be of
great value to scientists yet the Citation Index does
not adequately cover these contributions. Some
papers may be cited because of factual errors or they
may be even fabrications but the Index does not
reveal these details. There is no index for papers
withdrawn by journals or authors. Recently, Googles
PageRank index (PR) as well as a combination with
the Impact Factor (IF) such as PR IF = Y-factor have
been proposed (Ball P 2006 Nature [Lond 439:770).
Googles PageRank can be found at http://www.
iprcom.com/papers/pagerank/. There is no perfect
criterion for the impact of a scientists contribution
and the impact may also vary with time. citation
index; Butler L 2002 Nature (Lond) 419:877;
Lehmann S et al 2006 Nature [Lond] 444:1003,
http://scientific.thomson.com/products/wos/.
Impala (Aepyceros melampus melampus): 2n = 60.
Impaternate: Refers to offspring originated by parthe-
nogenetic reproduction. parthenogenesis
IMPDH (inosine-5-monophosphate dehydrogenase):
This is involved in lymphocyte replication. Myco-
phenolic acid (MPA), an approved immunosuppres-
sive drug, is its potent inhibitor (Desmoucelles C et al
2002 J Biol Chem 277:27036).
Imperfect Flower: This has either male or female sexual
apparatus, it is monoecious or dioecious but not
hermaphroditic. flower differentiation; hermaph-
rodite; monoecious; dioecious (see Fig. I13).
Figure I13. Asparagus flowers (After J.A. Huyskes &
J. Sneep)
Imperfect Fungi: These do not have a known sexual
mechanism of reproduction. fungal life cycles
Impetigo: This is a pus-forming skin infection caused by
the plasmid-carrying Staphylococcus aureus bacteria.
Implant: Denotes a grafted addition to the body or an
inserted artificial object or an implanted zygote.
Implantation: Refers to the attachment of the blastocyst
to the lining of the uterus after about a week of
fertilization and embedding it into the endometrium
(in humans). In mice lysophosphatidic acid receptor
(LPA3) and cyclooxygenase 2 (COX2) are involved
in the control of implantation and prostaglandin
biosynthesis (Ye X et al 2005 Nature [Lond]
435:104). blastocyst, uterus, prostaglandin,
cyclooxygenase, lysophosphatidic acid, Sta,
immunophilins, steroids; Paria BC et al 2002
Science 296:2185.
Importin and b: These are protein factors mediating the
passage through the nuclear pore by binding the
subunit to a nuclear localization sequence of a
protein, Ran-GTP. Importin has a positive regulatory
role in nuclear import and as a motor adaptor to move
molecules along the microtubules; it has negative roles
in mitotic spindle assembly, centrosome dynamics,
formation of the nuclear membrane, and nuclear
pore assembly (Harel A, Forbes DJ 2004 Mol Cell
16:319). nuclear pore, nuclear localization se-
quence, karyopherin, transportin, RNA export,
Ran, GTP, NuMA, TPX2; Mingot J-M et al
2001 EMBO J 20:3685; Gruss OJ et al 2001 Cell
104:83; structure: Matsuura Y, Stewart M 2004 Nature
[Lond] 432:872.
Impotence: This is the inability to initiate or maintain
erection of the penis due to organic or psychological
factors. nitric oxide, phosphodiesterase; Renaud RC,
Xuareb H 2002 Nature Rev Drug Discovery 1:663.
Impotence 979
I
Imprecise Alignment of DNA Strands: There is only
limited homology between the strands.
Imprinting: The expression of behavioral or other traits
may be influenced by the parental source of
chromosomes, i.e., the paternal and maternal gen-
omes may have a different effect (imprinting) on the
developing offspring because of the modification of
an allele by a cis-element or different methylation of
the sequence (Kaneda M et al 2004 Nature [Lond]
429:900). More than 150 mammalian genes are
subject to imprinting. Methylation also affects the
organization of the chromatin. The generation of
antisense transcript may be a means of imprinting
(Runte M et al 2001 Hum Mol Genet 10:2687). In
mice, the insulin-like growth factor gene (IGF-2)
transmitted through females is not transcribed (im-
printed, turned off) in most of the tissues and only the
one transmitted through the male is active. In
colorectal cancer there is 30% loss of imprinting
(biallelic expression) whereas in healthy individuals
this is only 10% (Cui H et al 2003 Science
299:1679). If the offspring receives a mutant copy
of the gene through the male and a normal copy
through the female, the heterozygote is crippled.
The choroid plexus (the brain tissue secreting the
cerebrospinal fluid) and the leptomeninges (the
innermost of the three membranes covering the brain
and the spinal cord) were not subject to IGF-2 gene
imprinting in mice. The IGF-2 is a single chain
polypeptide and an autocrine regulator of hormone
response and growth. The deletion of a silencer
element from the mouse Igf2 involves loss of
imprinting (LOI) and increases the chances of
multiple intestinal neoplasias in mice (Sakatani T
et al 2005 Science 307:1976). It appears that
methylation takes place in CG-rich islands of 200 to
1,500 base pairs and notably, several of the imprinted
genes are either in chromosome 11p or 15q in
humans, or in mouse chromosome 7. At the telomeric
end of mouse chromosome 7 there is a differentially
methylated CpG island (KvDMR) that is responsible
for imprinting several maternal genes. Intron 10 in
this island (Kcnq1) of KvDMR contains the pater-
nally expressed, non-coding antisense transcript,
Kcnq1ot1. When 244 base pair is deleted from there
the silenced genes are derepressed (Mancini-DiNardo
D et al 2006 Genes & Development 20:1268). The
maternally expressed gene, MEG3 is in human
chromosome 14q. In mouse chromosome 17, in
IGF-2 gene a 113-bp methylation imprinting box has
been identified. In mice imprinted genes are located at
nine regions in six autosomes. In human chromosome
15q11-q13 an imprinting center (IC) has been found,
involved in epigenetic resetting of this 2-Mb domain.
The IC is part of the promoter and the first exon of the
small nuclear ribonucleoprotein peptide N (SNRPN)
gene. When the untranslated H19 mouse gene was
disrupted, Ins-2 and Igf-2 genes 100-kb upstream
of H19were transmitted by the female. It has been
suggested (but not verified) that the chromosomal
choice of imprinting is determined by a competition
for a nearby enhancer. The actual H19 regulator, Afr1
affects the fetoprotein- transcription as well. Igf is
preferentially expressed in the male because a germ
line-inherited methylation silences the promoter of
the H19 gene. The 5 upstreamregion of H19 contains
an imprinting methylation signal (mark) in the male
rodent. This 42 bp element is conserved by
evolution. In the offspring, 27% higher weight was
observed compared to animals that received the same
chromosome fromtheir father. In mouse chromosome
11 mash-2 encodes a helix-loop-helix protein and it is
maternally expressed only in the placenta. If this gene
is deleted maternal lethality results but there is no
consequence if transmitted through the male. Placen-
ta-specific mouse genes are imprinted but in humans
their expression is biallelic due to the absence of
dimethylation of H3 histone lysine 9 and lysine 27
(Monk D et al 2006 Proc Natl Acad Sci USA
103:6623). If the mouse conceptus receives two
paternal or two maternal chromosomes 12, intrauteral
death results. Uniparental conceptuses are also
inviable. Normally, Ins-2 (insulin) is expressed
paternally in the embryo yolk but biparentally in the
pancreas. The tissue-specificity of imprinting of the
insulin-like growth factor is determined by which of
the four promoters of the gene was used. The human
gene, GNAS1 (chromosome 20q13.2-q13.3) displays
biallelic inheritance as well as imprinting in both
paternal and maternal directions, depending on the
promoter used and alternative splicing (Hayward B.
E. et al., 1998 Proc. Natl. Acad. Sci. USA 95:15475).
The upstream Nesp and Nesp/Gnasxl promoters are
methylated maternally and paternally. The down-
stream G protein -subunit is unmethylated with rare
exception. Upstream of G
s
there is an imprint mark
where methylation is established in oogenesis; thus
this imprinting is tissue-specific (Liu J et al 2005 Proc
Natl Acad Sci USA 102:5513).
Several paternally inherited X chromosomal genes
are inactive in early embryonic tissues. Although
differential inactivation is a common property of X
chromosomal genes, asynchronous replication has
been observed between homologous autosomes in
mice (Singh N et al 2003 Nature Genet 33:339). An
exception is the Xist gene, which is expressed only
from the paternally derived X chromosome. In some
cases the demonstration of true imprinting is difficult
because in human diseases the penetrance and
expressivity of the genes may vary widely. Imprinted
genes frequently carry special repeats, display
980 Imprecise Alignment of DNA Strands
I
unusual sex-specific rates of recombination and the
size of their introns are relatively short. Parthenogen-
esis may cause embryonic lethality in mouse if the
imprinted paternal genes are not expressed. During
tumorigenesis both the paternal and maternal copies
of the IGF-2 gene are expressed. Imprinted genes
usually replicate asynchronously from the rest of the
gene pool. Although it appears that expressed genes
replicate early, this rule does not hold for imprinting
because early replicating paternal genes may be still
silent. Imprinting appears mainly in mammals,
however imprinting-like phenomena have been
observed in the plant Arabidopsis (Choi Y et al
2002 Cell 110:33). Imprinting of the late-flowering
epimutation in the FWA gene of Arabidopsis is
limited to the endosperm and its activation depends
on the DNA glycosylase gene (DME) DEMETER
(Kinoshita T et al 2004 Science 303:521). Gene
MEDEA (MEA) is imprinted in the Arabidopsis
endosperm and it is activated by hypomethylation of
the maternal allele by the DME. METHYLTRANS-
FERASE (MET1) maintains CG methylation of the
MEA. The active MEA Polycomb-like complex
(MEA + FIE + PcG) in the endosperm silences the
paternal MEA allele by methylation (Gehring M et al
2006 Cell 124:495).
In mammals 0.11% of the genes may show some
degree of imprinting; in mice and humans only about
three dozen imprinted genes had been identified by
2000 (see Verona RI et al 2003 Annu Rev Cell Dev
Biol 19:237).
There is no generally valid interpretation of the
evolutionary utility of imprinting. It has been
hypothesized the imprinting has a dosage compensa-
tion purpose. Loss of imprinting may predispose to
sporadic colorectal cancer. Also, imprinting may
permit the expression of an oncogenic allele.
Alternatively, the conflict/kinship theory has been
proposed. According to this theory, if the female
produces offspring by more than one male during her
period of fertility, the more vigorous pregnancy
places greater demands on the female and thus
weakens the mother and thereby potentially harms the
future offspring sired by other male(s). To resolve this
conflict the mother activates on growth promoting
genes. The male silences genes that suppress growth.
Some of the facts seem to support this conflict theory,
others do not. According to the conflict hypothesis,
there should be no imprinting in monogamous
species. However, this expectation is not realized in
the monogamous Peromyscus polionotus rodents.
Imprinted genes, because of monoallelic expression,
may be at a higher risk to contribute to tumorigenesis
because a single recessive mutation may trigger
the process. methylation of DNA regulation of
gene activity, Xist (Tsix), IGF, Angelmans
syndrome, Prader-Willi syndrome, Beckwith-
Weidemann syndrome, Wilms tumor, Albright
hereditary osteodystrophy, Russel-Silver syn-
drome, insulin-like growth factor, myotonic
dystrophy, ataxia, MYF-3, KIP2, polar over-
dominance, VENTURE, diabetes mellitus, lyoni-
zation, parthenogenesis, co-suppression, snRNP,
dosage compensation, enhancer competition,
CTCF, imprinting box, parent-of-origin effect,
uniparental disomy, hydatidiform mole, obesity,
fetoprotein-, histones, epigenesis; Bartolomei
MS, Tilghman SM 1997 Annu Rev Genet 31:493;
Pfeifer K2000 AmJ HumGenet 67:777; Nakagawa H
et al 2001 Proc Natl Acad Sci USA 98:591; for
linkage analysis: Strauch K et al 2000 Am J Hum
Genet 66:1945; Spencer HG 2000 Annu Rev Genet
34:457; Reik W, Walter J 2001 Nature Reviews Genet
2:21; Mann JR 2001 Stem Cells 19:287; Ferguson-
Smith AC, Surani MA 2001 Science 293:1086;
Bourchis D et al 2001 Science 294:2536; Sleutels F
et al 2002 Nature [Lond] 415:810; Wilkins JF, Haig D
2003 Nature Rev Genet 4:359; de la Casa-Espern E,
Sapienza C 2003 Annu Rev Genet 37:349; Haig D
2004 Annu Rev Genet 38:553; Jiang Y-h et al 2004
Annu Rev Genomics Hum Genet 5:479, http://www.
mgu.har.mrc.ac.uk/research/imprinting/; catalog of
imprinted genes: http://igc.otago.ac.nz/home.html;
http://www.geneimprint.com; imprinted human gene
catalog: http://www.otago.ac.nz/IGC.
Imprinting, Behavioral: A response learned during the
early phase of life has a lasting effect on the behavior
of an animal throughout its life.
Imprinting Box: This is responsible for imprinting of
genes situated in the region 15q11-q13 of the human
chromosome (and in the homologous chromosome 7
segment of the mouse). The human imprinting box
extends to 200 bp of the promoter/exon 1 site of the
small ribonucleoprotein peptide N (SNRPN, 15q12)
gene and a 1-kb sequence about 35 kb upstream
including the short regions of overlap (SRO) of
Angelmans syndrome (AS-SRO) and Prader-Willi
syndrome SRO (PWS-SRO). The insulin-like growth
factor receptor gene (IGF2R) can act alone as a
methylation initiating imprinting box. Angelmans
syndrome, Prader-Willi syndrome, insulin-like
growth factor, imprinting; Shemer R et al 2000
Nature Genet 26:440.
Imprinting, Molecular: Biological molecules are coated
by polymers that preserve their three-dimensional
structure (imprint) in order to facilitate their manipu-
lation (breaking up at selective locations, fraction-
ation from complex mixtures).
Imprinting, Molecular 981
I
Imputation: Refers to estimation of the missing values
in a set of data using the information available. For
this purpose multiple regression may be used.
regression
In Silico Biology: Describes the identification of genes in
databases with the aid of bioinformatics. (Harris SB
2002 Embo Rep 3:511).
In Situ Hybridization (ISH): The DNA double strands
within the cells (chromosomes) are separated (dena-
turation) in cytological preparations on microscope
slides and labeled (radioactively or by fluorochromes
or by immunoprobes) and complementary DNA or
RNAstrands (probes) are annealed (see Fig. I14). The
cells are then visualized by microscopy as usual for
cytological microtechniques and can either be auto-
radiographed or viewed through fluorescence micros-
copy to ascertain the position of the hybridized
probe. Thus, the chromosomal location of molecular
markers can be determined. DNA hybridization,
somatic cell hybrids, probes, fluorochromes,
chromosome painting, FISH, immunoprobe,
nick translation, in situ PCR, PRINS, GISH,
MFISH; Pardue ML 1973 Cold Spring Harbor
Symp Quant Biol 38:475; Carpenter NJ 2001 Semin
Pediatr Neurol 8(3):135.
Figure I14. In situ hybridization
In Situ PCR: PCR technology is used within single cells.
The DNA is amplified followed by in situ hybridiza-
tion. By treating the cells with reverse transcriptase
before PCR enhances its utility. Such a procedure
permits the detection of cellular genic activity, viral
infection and the expression of just introduced
transgenes for gene therapy. PCR, RT-PCR,
PRINS, FISH; Kher R, Baccalao R 2001 Am J
Physiol Cell Physiol 281:C726.
In Vitro: The reaction or culture is carried out in a
glass vessel rather than in an intact cell or in natural
culture conditions, respectively such as in vitro
culture, in vitro fertilization or in vitro enzyme assay.
ART, cell genetics
In Vitro Fertilization (IVF): Extracted mammalian eggs
can be fertilized by competent sperms (AID or AIH)
outside the body and then surgically implanted into
the uterus. Such a procedure may have over 40%
chance of success and helps to overcome sterility in
many women with infertility problems caused by
factors other than the ova. In vitro fertilization
produces normal babies but the chance of having
non-identical twins is greatly increased if the
gynecologist implants more than a single fertilized
egg to assure a reasonable degree of success. When
single blastocysts stage (5 days old, in 175 indivi-
duals) and cleavage stage (3 days old, in 176
individuals) embryos were used for in vitro fertiliza-
tion in women under 36 years of age, the blastocysts
stage implantation resulted in higher pregnancy
(32%) than in at the cleavage stage (21.6%). In the
latter group there were two cases of monozygotic
twins (Papanikolaou EG et al 2006 New Engl J Med
354:1139). IVF of women above 35 years of age had
disappointingly low success (37%). The low rate
was attributed to increasing aneuploidy in older eggs.
Preimplantation elimination of chromosomally de-
fective eggs resulted in even lower frequency (25%)
of fertilization presumably because the removal of
single blastomeres for cytological tests harmed the
embryos (Mastenbroek S et al 2007 New England J
Med 357:9).
Concerns have been expressed about a slight
increase in genetic defects among the offspring
produced with the aid of these techniques, particular-
ly the ICSI (Powell K 2003 Nature [Lond] 422:656;
Gicquel C et al 2003 Am J Hum Genet 72:1338). IVF
has applied significance in animal breeding. For
example, from the ovaries of cows eggs can be
retrieved in slaughterhouses and after in vitro
fertilization can be re-implanted into any (even some
sterile) cows. Through this procedure more beef can
be produced. There is an opportunity to obtain more
offspring from genetically superior individuals of
domestic animals by the use of surrogate mothers.
It has applications in wildlife preservation of
endangered species (in zoos) or in species with an
unsatisfactory natural rate of reproduction. twin-
ning, artificial insemination, insemination by
donor, preimplantation genetic, GnRFA, ART,
ICSI, test tube baby; Elder K, Dale B 2000
In Vitro Fertilization, Cambridge Univ. Press, New
York; Ozturk O et al 2001 Hum Repr 16:1319.
In Vitro Mutagenesis: Mutation is produced in isolated
DNA sequences that is then re-introduced into the
cells by transformation. localized mutagenesis,
site-specific mutagen-esis, gene replacement
TAB mutagenesis, transformation genetic, cas-
sette mutagenesis, Kunkel mutagenesis, PCR-
based mutagenesis, doping nucleotides; Lehoux
DE et al 2001 Curr Opin Microbiol 4:515.
982 Imputation
I
In Vitro Packaging: Recombinant DNA equipped with
the phage cos sites and genes required for
packaging (origin of replication and other sequences
of about 46 kb at both cos neighborhoods) can
accept inserts so that the total length remains in
the range of 3752 kb, can be packaged into
phage capsids that may infect E. coli and yeast cells
and bring about transformation. Similar procedures
are applicable to other systems. cosmid vector,
lambda phage; Okimoto T et al 2001 Mol Ther
4(3):232.
In Vitro Protein Synthesis: in vitro translation systems
In Vitro Translation: rabbit reticulocyte translation
assay, wheat germ translation, translation in vitro,
oocyte translation
In Vivo: The process takes place in intact cells or in the
tissues of a living organism or cell. in vitro,
ex vivo
Inactive-X Hypothesis: Lyons hypothesis
Inborn Error of Metabolism: This is a historical term for
biochemical genetic defects. Generally mutation in
single genes blocks or changes the metabolic path-
ways at a single specific step. The photograph shows
the response of an auxotrophic mutant of Arabidopsis
unable to synthesize the pyrimidine moiety of
thiamine. On basal medium it germinates but fails
to grow; its growth is fully restored on the appropriate
pyrimidine, PYand thiamine, TH. A slight growth is
also seen on the thiazole moiety of thiamine TZ
(Rdei, 1965 unpublished). The consequences of the
mutation may be alleviated either by providing the
missing compound or by avoiding the supply of the
accumulated precursors that cannot be further
processed because of the defect in the enzymatic
step. Although a single enzymatic step is often
involved, the lack or overproduction of a metabolite
can affect more than a single metabolic process in
complex diseases (see Fig. I15). Inborn errors of
metabolism include defects in quantitative genes and
other intrauterine lesions and infections. In plants
auxotrophic mutations are very rare; the number of
identified metabolic defects due to genetic causes
(mutation, deletion, insertion, rearrangement) is
increasing in humans. Defects in humans may be
caused by the absence or decrease of a metabolite, the
adverse effect of accumulated precursor(s), overpro-
duction, faulty regulation of a pathway and/or adverse
effects on more than one pathway in a metabolic
network. The defect can be cell autonomous, i.e.,
affects only a particular cell or it may be non-
autonomous and its consequence spreads to other
tissues either by diffusion or secretion and active
transport. The presence of a metabolic defect can be
discovered by simple means; Garrod identified
alkaptonuria by the brown spots on the diapers of
newborns. The nature of the defect can be identified
by chemical analysis, the use of isotope or fluoro-
chrome labeled metabolic tracers, enzymes assays of
body fluids or tissues, by microarray hybridization,
two-dimensional electrophoresis or mass spectrome-
try, nuclear magnetic resonance spectrometry (NMR)
and other tools of proteomics. The treatment of the
disease varies according to its nature. Phenylketon-
uria or fructose intolerance requires metabolic
restrictions, in Wilson disease avoidance of copper
helps. In other cases dietary supplements can help,
e.g., consuming starch in glycogen storage diseases
or taking biotin in biotidinase deficiency or avoiding
fasting in some forms of fatty acid metabolism
disorders. In Gaucher disease enzyme replacement, in
Hurlers syndrome enzyme replacement and bone
marrow transplantation are used. For several diseases
somatic gene therapy is available. The implantation
of embryonic stem cells may be helpful for a range of
human lesions and disease. Avoidance of several
diseases is possible by genetic counseling, screening
for carriers and neonatal screening. Screening
newborns for inborn metabolic errors by tandem mass
spectrometry revealed a frequency of 1.57 10
4
(Wilcken B et al 2003 New England J Med 348:2304).
auxotrophy, one gene one enzyme theorem,
biochemical genetics; Garrod AE 1902 Lancet
2:1616; see individual entries for diseases and other
terms; excellent review: Lanpher B et al 2006 Nature
Rev Genet 7:449.
Figure I15. Arabidopsis py mutants respond only to the
pyrimidine moiety of the thiamine or to thiamine
Inbred: Denotes a line developed by continued
inbreeding until the majority of the genes become
Inbred 983
I
homozygous. In mice usually 20 generations of
brother sister (or parent offspring) mating is done
to produce such lines. In species where self-fertiliza-
tion is feasible (e.g., plants) ten generations of
inbreeding results in more than 0.999% homozygosi-
ty (1 0.5
10
), unless the genes are very tightly linked
in repulsion. coefficient of inbreeding, coiso-
genic, congenic, substrain, subline, linkage
disequilibrium
Inbreeding: Refers to mating among biological rela-
tives, including self-fertilization, brother- sister
mating and mating with ancestors or offspring.
coefficient of inbreeding, inbreeding in autopo-
lyploids, inbreeding and death rates, inbreeding
and population size, inbreeding progress; Fisher
RA 1949 The Theory of Inbreeding, Oliver & Boyd,
Edinburgh.
Inbreeding and Death Rates: Inbreeding results in
homozygosity of deleterious and lethal genes which
in turn increase spontaneous abortions, infant mortal-
ity and the frequency of hereditary diseases (see Table
I1). The frequency of the adverse consequences
depends upon the frequency of these undesirable
genes in the population concerned and the degree of
inbreeding. When infant mortality in first cousin
marriages and that in the general population mar-
riages is compared the frequency in the former is
almost double. Some of the variation within columns
may also be due to random statistical error:
In a recent analysis the excess death rate up to
age 10 of the progeny of first cousin marriages in
Japan, Pakistan, India and Brazil combined appeared
to be 4.4%. coefficient of coancestry, inbreeding
coefficient, inbreeding depression, incest, ge-
netic load, lethal equivalent
Inbreeding and Linkage: The probability of homozy-
gosity after backcrossing to an inbred line varies
according to the intensity of linkage and the number
of backcrosses performed (see Table I2).
Inbreeding and Population Size: Inbreeding increases
more in smaller populations than in large ones. The
increase can be reduced by controlled mating, i.e.,
when the mating pairs are selected from different
families or if an equal number of mates is selected
from each family of the herd. The rate of inbreeding
(
F
) = 1/2N
e
. If the actual size of the population
is say 10, then
F
= 1/(2 10) = 0.05. In case
the effective population size is only 0.75 of the
total population then
F
= 1/2N
e
= 1/(2 10 0.75)
= 1/15 = 0.066. The coefficient of inbreeding becomes
F
g
=1 (1
F
)
g
where F
g
is the inbreedingcoefficient
of the g
th
generation and
F
is the rate of inbreeding.
inbreeding coefficient, inbreeding depression,
inbreeding rate, population size effective
Inbreeding Autopolyploids: Since autopolyploids have
more alleles present per locus, homozygosity at a
locus is achieved only after a larger number or several
generations. Many of the autopolyploid species
reproduce by self-fertilization and the deleterious
consequences of inbreeding have been eliminated by
natural selection. Since many of the crop plants are
polyploid, plant breeders rely on crossing for
improvement. In allopolyploids the consequences of
inbreeding may vary according to the species. A
comparison of the proportion of homozygotes in
diploids and tetraploids of the initial genetic con-
stitutions Aa, Aaaa and AAaa, respectively, after five
generations of self-fertilization is presented in the
table (see Table I3).
Table I1 Infant mortality and inbreeding
Ethnicity First-cousin
marriages %
General
population %
Canadian 8.8 4.1
French 9.4 4.4
Japanese 6.2 3.9
Swedish 8.5 4.0
(After Fraser, F. C. & Biddle, C. J. 1976. Am. J. Hum. Genet.
28:522.)
Table I2 Arriving at homozygosity after backcrossing as a function of recombination frequency
Recombination Number of Backcrosses 2 3 6 9 12
0.5 0.500 0.750 0.969 0.996 0.999
0.3 0.300 0.510 0.832 0.942 0.980
0.1 0.100 0.190 0.409 0.569 0.686
(After Klein, J. 1975. Biology of the Mouse Histocompatibility-2 Complex. Springer, Berlin.)
984 Inbreeding
I
Inbreeding Coefficient: Denotes the probability that two
alleles at a locus in an individual are identical by
descent from a common ancestor, i.e., the chance that
an individual is homozygous for an ancestral allele
by inheritance (not by mutation). The inbreeding
coefficient for second cousins is 1/64 and for third
cousins it is 1/256. In case only one of the parents
is common at the starting generation the inbreeding
coefficient of half-sibs at uncle-niece or aunt-nephew
marriage is 1/16, for first cousins 1/32, for second
cousins 1/128, and for third cousins 1/512.
Consanguinity (coancestry) is a similar concept but
the coefficient of coancestry indicates the chances
that one allele in two individuals would be identical
by descent. F symbolizes the coefficient of inbreed-
ing. The calculation of F is based on the fact that in a
diploid at each locus there are two alleles and only
one is contained in any gamete (either one in
a particular egg or sperm). Thus, each individual
has 0.5 chance for passing on a particular allele to a
particular offspring. To illustrate the method of calcu-
lation examples will be discussed (see Fig. I16).
Brother (X) and sister (Y) have two common parents
(W) and (V). An offspring of the mating (X) (Y)
(X)(I) or (W)(Y)I), therefore his chances
for homozygosity for one allele derived from (W) is
0.5
2
= 0.25. In other words, in F
2
the chance is 1/4 for
homozygosity for any allele according to the
Mendelian law. In a half-brother and half-sister
progeny grandparent (A) can transmit a particular
allele to (I) either through (B) or (C) parents and the
inbreeding coefficient of (I) is 0.5
3
= 1/8 because
three individuals are involved in the transmission
route (A), (B) and (C). Similarly, the inbreeding
coefficient of other types of matings can be calculated
as indicated in the chart. In half first cousin mating
individuals (C), (B), (A), (E) and (D) are involved in
the transmission path, each with a 0.5 chance thus
the coefficient of inbreeding becomes 0.5
5
= 0.03125
= 1/32. In two generations of brother-sister matings
(see scheme 6), the transmission of alleles may follow
the routes [E-C-F, F-D-E], {E-C-A-D-F, F-D-B-C-E,
E-D-A-C-F and F-C-B-D-E}, i.e., [2] and {4} paths
of [0.5]
3
and {0.5}
5
, respectively. The coefficient of
Table I3 Progress of inbreeding in autotetraploids compared to diploids
Generation Aa (diploid) Aaaa Chrom. segr.
1
Aaaa Max. equat.
2
AAaa Chrom. segr.
1
AAaa Max. equat.
2
F
2
0.500 0.250 0.295 0.050 0.099
F
3
0.750 0.380 0.460 0.194 0.285
F
4
0.875 0.493 0.581 0.326 0.442
F
5
0.938 0.558 0.674 0.438 0.566
F
6
0.969 0.648 0.747 0.531 0.662
(After Burnham, C. R. 1962. Discussions in Cytogenetics. Burgess, MN.)
1
Chromosome segregation indicates that the gene is absolutely linked to the centromere.
2
Maximal equational segregation occurs when the gene segregates independently from the centromere.
A
1 2 3 4 5 6
A A
A
A
B
B
B
B B
A B
E
E F E F
C D
C D
C D
C D
C D C
1/8
I I I I I I
Half
Brother
&
Sister
Half
First
Cousin
First
Cousin
Grandson
&
Daughter
Full Brother
& Sister
Two Generations
Brother-Sister
0.5
3
1/32
0.5
5
1/16
0.5
5

+ 0.5
5
0.5
5
1/4
0.5
3
+ 0.5
5
3/8
2(0.5)
3
+ 4(0.5)
5
1/16
Figure I16. Calculation of the coefficient of inbreeding on the basis of the paths of allele transmission
Inbreeding Coefficient 985
I
inbreeding is 2[0.5]
3
+ 4{0.5}
5
= 0.375 = 3/8. If there
are multiple paths through the same ancestor, all the
paths through the shared ancestors must be included
in the calculation with the precaution that the same
ancestor must be counted only once in the same path.
The method can be illustrated by another example
where (Z) and (U) are the common ancestors and
again the inbreeding coefficient of individual (I) is
sought. There are two routes through (Z): T-Z-L-K
and T-Z-M-K and also two paths through (U): K-M-
U-T and K-L-U-T. Each of these four paths involves
four ancestors contributing genes to (I). Therefore,
the coefficient of inbreeding of (I) is 4(0.5)
4
= 0.25 =
1/4. Under practical conditions of breeding far more
complicated schemes may be encountered yet their
solution can be sought in terms of these simple
examples. It is easier to determine the loops of gamete
contribution by working backwards from the critical
individual, (I) in this case. It is conceivable that
the common ancestors are not completely unrelated,
contrary to the assumption in the calculations here,
but they may have some degree of relatedness and
their inbreeding coefficient, F
A
(ancestral coefficient
of inbreeding) must also be taken into account.
Therefore, the general formula for the coefficient
of inbreeding is F = [(0.5)
n
(1 + F
A
) where is the
sum of the paths through which an individual
can derive identical alleles from his ancestors and
n = the number of individuals in the paths. 1 + F
A
is the correction factor for the inbreeding coefficient
of the common ancestor in the path. Calculating
the coefficient of inbreeding may not only be very
important in a breeding project, but it may also be
relevant to human families. It is assumed that the
frequency of a recessive genetic disorder is q
2
= 1
10
6
and if the population is in a genetic equilibrium
the frequency of that allele is q =

q
2
_

0:000001
p
.
Then the risk related parents face of having an afflicted
child is: q
2
(1 F) + q(F). Since the inbreeding
coefficient of the offspring of first cousins is F=
1/16 = 0.0625 (see Figs. I17 and I18), after
substitutions one obtains: 0.000001 0.9375)
+(0.001 0.0625) 0.000063. Since 0.000063 is
63 fold higher than 0.000001 (the frequency of
individuals with this affliction in the general popula-
tion), first cousin parents are at a >63 fold greater risk
than unrelated parents to have an offspring afflicted
with a hereditary disease that has a gene frequency of
0.001. In some cases inbreeding may be detected by
DNA fingerprinting or by nucleotide sequence of the
genome. F, coefficient of coancestry, consan-
guinity, relatedness degree, inbreeding progress,
inbreeding rate, fixation index, genetic load,
homozygosity mapping, DNA fingerprinting,
inbreeding depression; Fisher RA1965 The Theory
of Inbreeding, Academic Press, New York.
Full: 1/32
First cousin
once removed
Second cousin
once removed
Half: 1/64
Full: 1/128
Half: 1/256
Figure I17. Coefficient of inbreeding among cousins
Z U
L
M
K
T
I
Figure I18. Multiple paths of allele transmission
Inbreeding Depression: When inbreeding and the
deleterious recessive genes become homozygous,
the viability, vigor and fitness of the individuals and
the population decline in normally outcrossing or
dioecious or monoecious species. The degree of
depression varies according to the species and traits
affected. Some degree of inbreeding takes place in
human populations. Inbreeding is common (50%)
in parts of Pakistan and India where uncleniece or
first cousin marriages are often seen (see Fig. I19). In
Japan and South America inbreeding varies between
1% and 10% whereas in Europe and North America
consanguinity is about 1% except in some isolated
religious groups. The major religions (Christianity,
Judaism, Buddhism and Zoroastrian) approve first
cousin marriages with some restrictions. In Sweden
even half-sibs can legally marry if the government
approves of such a union. In eight states of the US
first cousin marriage is considered criminal whereas
in 22 states it is illegal. In ancient Egypt the pharaoh
frequently married his sister; this probably explains
the relatively large number of mummies of infants at
the burial places. Consanguineous marriages increase
homozygosis and the frequency of inborn errors of
metabolism, malformations and other physical or
mental genetic load. In many societies consanguine-
ous marriages are preferred to ensure that the family
estate remains intact. As industrialization and urbani-
zation advance the frequency of consanguineous
marriages declines. In animal husbandry inbreeding
is used with the purpose of fixation of desirable traits.
In plant breeding, maximal hybrid vigor of some
986 Inbreeding Depression
I
crops (heterosis) is achieved by using inbred lines.
inbreeding progress, inbreeding coefficient,
inbreeding and death rates, heterosis, con-
trolled mating, Marfan syndrome; geographic
distribution of human consanguinity: Bittles AH
2001 Clinical Genet 60(2):89.
Figure I19. Pharaoh and wife, close relatives (Cour-
tesy of C.S. Gowans)
Inbreeding, Progress of: The proportion of homozy-
gosity of any selfed or inbred generation for any
number of allelic pairs can be computed by the
formula (see Fig. I20):
100
75
50
15
5
1
22 3 4 5 6 7 8 9 10
10
F
%

H
e
t
e
r
o
z
y
g
o
t
e
s
25
Figure I20. Consequences of repeated inbreeding
(selfing) on the frequency of heterozygotes for 1, 5, 10
and 15 allelic pairs. (Redrawn after Jones, D.F. 1925
Genetics in Plant and Animal Improvement. Wiley,
New York)
[1 + (2
g
1)]
n
where g is the number of generations
selfed (note: e.g., by F
5
there are 4 selfings because F
1
is the result of crossing) and n is the allelic pairs
involved. An example of expansion of the binomial in
case of 3 pairs of alleles in F
5
:
[1+ (2
4
1)]
3
= [1 + (16 1)]
3
= 1
3
+ 3(1)
2
(15) + 3
(1)(15)
2
+ 1(15)
3
or rewritten as
1
3
(15)
0
+ 3 (1)
2
(15)
1
+ 3(1)
1
(15)
2
+ (1)
0
(15)
3
where the first exponent in each term indicates the
number of heterozygous genes and the second
exponent denotes the number of homozygous genes
in each class of individuals. In this example 1 is
heterozygous for all 3 loci and homozygous for none
(3 15). Further, 45 is heterozygous for 2 loci and
homozygous for 1 (3 15
2
), i.e., 675 is heterozygous
for 1 locus and homozygous for 2. 1 15
3
, i.e., 3375 is
heterozygous for none of the 3 loci but is homozygous
for all 3 in a total population of 4096 (1 + 45 + 675 +
3375 = 4096). heterozygote proportions, binomial,
coefficient of inbreeding, fixation index
Inbreeding Rate: This is determined as
F
= 1/(2N
e
),
where N
e
= effective population size. If the actual size
of a population is 10 then
F
= 1/(2 10) = 0.05. In this
computation the effective population number is
considered to be equal to the total number. Under
practical circumstances this is rarely the case. If it is
assumed that the effective size is only 3/4 of the actual
number then
F =
1/(20 0.75) 0.066, a higher
fraction. The coefficient of inbreeding can also be
calculated as: F
g
=1 (1
F
)
g
where g =the number of
generations of inbreedingandF=inbreedingcoefficient.
Accordingly, after 25 generations, F
25
= 1 (1
0.066)
25
= 1 (0.934)
25
0.819 whereas if 10 is the
effective size, F
25
= 0.723 in this hypothetical case.
effective population size, inbreeding progress,
inbreeding coefficient, fixation index
INCENP: sister chromatid cohesion
INCEST: Refers to legally prohibited sexual intercourse
between close (biological) relatives. Incest is primar-
ily a legal, ethical and moral concept. From the
viewpoint of genetics, the consanguinity of the
parents is considered and legal restrictions may not
be adequate to avoid the deleterious consequences of
such matings for the offspring. In ancient Egypt the
pharaohs frequently (and legally) married their sisters
and this may explain the large number of mummies of
children at the burial places. Relatively scarce data
are available on children of first-degree relatives
(parent child, brother sister) yet it is clear that
nearly 40% of them have more or less severe physical
and/or mental defects. Interestingly, in populations
where uncleniece and cousin marriages have been
practiced for centuries the number of birth defects
is not as high as would be expected. Apparently,
the inbreeding continued for many generations
purged the gene pool of the most deleterious
alleles that are maintained at random mate selection.
coefficient of coancestry, coefficient of
inbreeding, genetic load
INCEST 987
I
Inchworm Model: During transcription the RNA
polymerase is flexibly connected to the template.
The front-end domain is tightly associated with the
DNA (10 bases) and that is followed by a loose
association (1520 bases), including the catalytic
domain, which in turn is followed by another tight
association (10 bases) to the transcript. Thus, the
movement of the polymerase displays a variable
discontinuous pattern. Asomewhat similar mechanism
is seen in an end-to-end template switching. When the
nucleotide supply is lowthe polymerase can jump from
a single-strand template to 79 bases of another linear
double-stranded DNA. The upstream electrostatic
interaction involves the C-end of the subunit whereas
the downstreaminteraction involves the N-end of the
subunit of the polymerase. The polymerase ternary
complexmayalsomove backwardand the catalytic site
may be involved in the cleavage of the RNA strand.
Kinesin may move either by inchworming or by the
hand-over-hand mode. RNA polymerase, tran-
scription, transcript elongation, protein synthesis,
promoter clearance, TCF, kinesin; Uptain SM
et al 1997 Annu Rev Biochem 66:117.
Incidence: This is the frequency of occurrence of a
genetic alteration or disease in a population. preva-
lence, incidence and prevalence database: http://
library.dialog.com/bluesheets/html/bl0465.html.
Incipient Species: Refers to a group of organisms in the
process of speciation. speciation, evolution
Inclusion Body (IB): This is a protein aggregate in
E. coli cells expressing at a high rate some foreign
gene(s), in the presence of amino acid analogs or
antibiotics. They appear to be the products of
processing of proteins and degradation of defective
polypeptides. These proteins can be examined by a
phase contrast microscope and can be concentrated
by the centrifugation of lysed or sonicated cells.
Some RNA viruses replicate within cytoplasmic
inclusion bodies. Inclusion bodies are formed by
the aggregation of huntingtin and other proteins
in Huntingtons chorea. In this disease, the role of
inclusion bodies has been controversial in as much as
both deleterious and beneficial effects have been
reported. Recent evidence has indicated that IB
formation reduces the level of huntingtin and the
risk of neuronal death (Arrasata M et al 2004 Nature
[Lond] 431:805). In mice shortstop inclusions
themselves may not be pathogenic as such but they
may enhance excitotoxicity (caused by neurotoxic
glutamate-like substances) and thus mediate neuro-
degeneration (Slow EJ et al 2005 Proc Natl Acad Sci
USA 102:11402). phase contrast microscope, so-
nicator, Ibp, Huntingtons chorea; Rattenholl A
et al 2001 Eur J Biochem 268:3296.
Inclusion Body Myopathy (cytoplasmic body myopathy):
This is a late-onset non-progressive muscle weakness.
The muscle fibers contain microscopically visible
inclusions in the cytoplasm. Both autosomal dominant
and recessive inheritance have been reported. Domi-
nant inclusion body myopathy 3 (IBM3, 17p13.1)
displays rimmed vacuoles and ophthalmoplegia. The
recessive IBM2 (9p12-p13) shows amyloid-like inclu-
sions. The latter is relatively frequent among Jews
of Kurdish and Iranian origin. This disease is caused
by mutation in the UDP-N-acetylglucosamine-2-
epimerase/N-acetylmannosamine kinase. amyloid,
ophthalmoplegia, Lewy body; Eisenberg I et al
2001 Nature Genet 29:83.
Inclusive Fitness: This is a type of altruistic behavior.
Parents defend their childrenat their own riskfor
the sake of maintenance of their genes, which the
offspring shares with them. This altruistic behavior is
positively correlated with the degree of relationship.
According to Hamiltons rule the closer the genetic
relationship, the greater is the degree of altruism. R.A.
Fisher and J.B.S. Haldane discussed this phenomenon
earlier. Siblingson the averageare expected to
share half of their genes and fitness whereas cousins
share only 1/4. Hamiltonian medicine shows that
infection caused by multiple microbial strains may
either increase or decrease virulence. In some instances
large colonies are formed which because of kin
selection (i.e., altruistic behavior among relatives)
increase the harm to the host. In other instances the
different microbes turn against each other and reduce
the risktothe host (Foster KR2005Science 308:1269).
While brushingteethdifferent bacteria are mixedonthe
gums which reduces the extent of dental corrosion.
fitness, altruistic behavior, kin selection,
inbreeding coefficient, microbiome; Sundstrom
L, Boomsma JJ 2001 Heredity 86(pt 5):515; Griffin
AS, West SA 2003 Science 302:634.
Incompatibility: See for plants S alleles, incompati-
bility alleles for mammals. ABO blood group, Rh
blood group, erythroblastoma, immune tolerance,
histocompatibility [in tissue and organ transplanta-
tion], plasmid incompatibility, fungal incompati-
bility, heterokaryon incompatibility, cytoplasmic
incompatibility, maternal tolerance, eclampsia;
incompatibility mechanisms among plants: Bomblies
K, Weigel D 2007 Nature Rev Genet 8:382.
Incompatibility Alleles: Self-incompatibility in a large
number of plant species (tobacco, clover, crucifer,
fescue, beet, cherry, etc.) may prevent self-
fertilization or formation. The number of different
incompatibility alleles may run into hundreds in some
species. A plant pollen carrying a particular incom-
patibility allele may not successfully develop a pollen
988 Inchworm Model
I
tube in the stylar tissue of the same genetic
constitution but may successfully fertilize another
plant of a different allelic constitution (see Fig. I21).
A sperm with a S1 allele is incompatible with a stylus
of S1S1 type but may fertilize a S2 egg. In a S1S2
heterozygote neither a S1 nor a S2 sperm may be
successful but they have no barriers in S3S3 plants. In
some species compatibility may be determined by the
sporophytic tissue; in a S1S2 stylus, if the S2 allele is
dominant, the S1 pollen may be successful and
produce a S1S1 seed. In some cases the S1S2 pollen
of a tetraploid plant may be compatible with a S1S1
egg if the S2 allele is dominant. In the Brassicaceae
the S alleles extend to several hundred kb and include
several closely linked transcriptional units, often
referred to as the S haplotype.
Incompatibility may also be based on different
timing of pollen release and receptivity of the stigma.
Compatible combinations may arise through induced
mutations. Heterostyl (different height of the stylus
and stamen) may also prevent self-fertilization.
S-specific glycoproteins and ribonuclease enzymes
cause self-incompatibility. In the Brassicaceae two
tightly linked genes, mediating incompatibility,
encode the S locus receptor serine/threonin protein
kinase (SRK) and the secreted glycoprotein (SLG,
431 amino residues). It is assumed that a pollen-born
ligand ties SLR and SLG into a signaling complex
that prevents germination or the growth of the pollen
tube on the stigma or in the style. An interesting
observation is that a SRK incompatibility protein
provides protection against Pseudomonas syringae
infection. In the Solanaceae the S locus encodes
another type of glycoprotein with ribonuclease
activity (S-RNase) and this ribonuclease may inhibit
the growth of the incompatible pollen tubes. In wild
poppy (Papaver rhoeas) Ca
2+
signaling inhibits
incompatible pollen tip growth and actin depolymer-
ization and apoptosis follow (Thomas SG et al 2006 J
Cell Biol 174:221).
The Hmr (hybrid male rescue) gene determines
hybrid incompatibility among the sibling species of
Drosophila melanogaster (Barbash DA et al 2003
Proc Natl Acad Sci USA 100:5302). It encodes a
MYB-related DNA-binding transcriptional regulator
protein. The gene evolved by base substitutions,
deletions and insertions especially in the DNA-
binding domain may be a main factor of sexual
isolation and speciation. mentor pollen effect,
male sterility, apomixis, gametophyte, genet-
ic load, fungal incompatibility, Rh blood group,
ABO blood group, self-incompatibility, MYB
oncogene, actin; Wang X et al 2001 Plant Physiol
125:1012.
Incompatibility Load: genetic load
Incompatibility, MotherFetus: During gestation the
paternal alloantigens of the fetus should not permit an
immune reaction by the mother to ensure the survival
of the fetus. Several mechanisms are believed to be
involved in this. It has been observed that HLA-G,
FasFasL or TRAILLTRAILR control apoptosis of
maternal leukocytes during pregnancy. Indolamine
2,3-dioxygenase, a tryptophan-catabolizing enzyme,
suppresses maternal T cell activity and rejection of
allogeneic fetus (Munn DH et al 1998 Science
281:1191). The complement regulator decay accel-
erating factor protein, Crry in the placenta controls
tolerance in mice and humans (Xu C et al 2000
Science 287:498). The inhibitory co-stimulatory
programmed cell death (PD1) protein and its ligands
(PL1, PDL2) are also critically involved (Guleria I
et al 2005 J Exp Med 202:231).
Incompatibility is genetically determined in eryth-
roblastosis fetalis in the case of wrong Rh allele
combinations or to some extent in other blood groups.
Incompatibility may be mediated by the activation of
the complement. Decay accelerating factor (DAF)
inactivates the C3 complement component conver-
tase protein that activates C3. Membrane cofactor
protein (MCP) is required for degradation of the
activated C3 and C4. In murines a regulatory protein
suppresses C3 deposition but if it becomes homozy-
gous for an inactive mutation fetal loss may ensue.
erythroblastosis fetalis, genetic load, killer
cells, complement, decay accelerating factor,
MCP, incompatibility, Rh blood group,
eclampsia, HLA, Fas, TRAIL, apoptosis,
allogeneic
S
1
S
1
S
1
S
1
S
1
S
2
S
2
S
2
S
2
S
1
S
2
S
2
S
1
S
2
2x
(A) (B)
4x
Figure I21. (A) The compatibility of the diploid pollen in a
duplex tetraploid plant. (B) Incompatibility associated with
dimorphismof style and stamen length. (After Linskens HF,
Kroh M 1967. Encyclopedia of Plant Physiology. Vol. 18.
Springer. Berlin, Germany)
Incompatibility, MotherFetus 989
I
Incompatibility Plasmids: These utilize the same system
of replication and cannot co-exist. When they are
introduced into the bacterial cell they have to compete
with each other and consequently one is eliminated.
Plasmids (phages) that carry the same replicon belong
to the same incompatibility group. RNA I, RNA II
and the Rop protein determine incompatibility. There
are more than 30 plasmid compatibility groups.
RNA I; Miller CA, Cohen SN 1993 Mol Microbiol
9:695.
Incompatibility, Vegetative (somatic incompatibility):
Refers to the blocking of hyphal fusion and the
formation of heterokaryons. hypha, heterokary-
on, fungal incompatibility
Incomplete Digestion: The reaction with restriction
enzymes is terminated before all potential cleavage
sites are cut. A greater variety and a few large
fragments are cut because some neighboring se-
quences are not cleaved apart. restriction enzymes
Incomplete Dominance: This is also known as semi-
dominance and it is observed when the expression of
the gene does not entirely mask or prevent the
expression of the recessive allele at the same locus in
a hybrid. dominance, epistasis
Incomplete Linkage: Recombinationtakes place between
or among the syntenic genes in question. recombina-
tion, crossing over, synteny, linkage
Incongruence: This may be construed as evidence of
horizontal gene transfer because the variation at
certain loci is higher than that of the flanking regions.
transfer lateral; Farris JS et al 1995 Cladistics
10:315.
Incontinentia Pigmenti (Bloch-Sulzberger syndrome,
IP1): Human X-linked (Xp11) dominant marble-
cake-like dark pigmentation on the skin of the trunk
is generally preceded by an inflammation. It may
begin soon after birth and may fade by the age of 20.
The condition may be associated with eye, tooth,
bone and heart anomalies. Most of IP2 cases are
apparently due to mutation/chromosomal breakage at
the gene NEMO (NF-B essential modulator)/IKK
(IB kinase-) closely linked to antihemophilia factor
VIII at Xq28. Mutation/chromosome breakage in
both IP1 and IP2 is lethal in the case of males before
or around birth whereas in the heterozygous females
survive to adulthood and the severity of the symptoms
varies. Some of the rare cases of males with IP1 may
be mosaics or of XXY constitution. hypomelanosis
of Ito, pigmentation defects, erythrokeratodermia
variabilis, antihemophilic factors, NF-B, ec-
todermal dysplasia, NEMO; Aradhya S et al 2001
Hum Mol Genet 10:2171.
Incorporation Error: This is a mechanism of mutation
when a nucleic acid base analog or a wrong base is
inserted into nucleic acid during replication. As a
consequence one base pair replaces another. The
meaning of the codon may change and it appears as a
visible mutation if the codon change leads to an
amino acid substitution at a critical site in the protein.
For example: during replication a 5-bromouracil is
inserted into the DNA at a C site resulting in a BrU
G base pair. During the next replication the BrUA
pair is formed and during a subsequent replication a
T=A pair is substituted at a site where originally a
CG pair existed. replication error, base substitu-
tion mutations, hydrogen pairing; Freese E 1963 in
Molecular Genetics, p. 207, Taylor JH ed. Acad.
Press, New York.
Incremental Truncation for the Creation of Hybrid
Enzymes (ITCHY): iterative truncation
Incross: Refers to hybridization between two strains
that have the same genetic background.
Indel: An insertion or deletion in the DNA nucleotide
sequences can be illustrated by the simple example
below the alignment score (see Fig. I22). Pr = p
3
q
2
r
1
where p is the probability of identity (match), q is the
probability of substitution (mismatch) and r is the
probability of an indel. The alignment score can be
derived as follows:
S + log Pr = 3(log p) + 2(log q) + (1(log r) and S =
S -nlog s = S - 6(log s) S = a constant satisfying
log(p/s) = 1). And S = 3 - 2 - 1 where = log(q/s),
= log(r/s) and S = number of identities - number
of substitutions - number of indels. Computer
programs based on high level mathematics that
cannot be presented here can resolve the problem.
TT AAG C
Indel
CC
Mismatch
A C
Match
G
Figure I22. Indel
The average size of indels among taxonomically
diverse species was found to be about 36 nucleotides
but some indels extended to 10 kb. The frequency of
unpaired nucleotides due to indels was almost three
times more than those caused by base substitutions
(Britten RJ et al 2003 Proc Natl Acad Sci USA
100:4661). Comparison of the DNA sequences
between the corresponding human chromosome 21
and chimpanzee chromosome 22 revealed that the
single nucleotide mismatches represented only 1.44%
of the sequence whereas 68,000 small or large
990 Incompatibility Plasmids
I
stretches of indels were found. The initial map of
human indels contains 415,436 unique polymorph-
isms within the range of 1 to 9989 base pairs. On an
average, there was 1 indel/7.2 kb human DNA.
Further, 148,000 indels were found within genes and
5542 of these were within promoters or exons where
they had the maximal effects on function (Mills RE
et al 2006 Genome Res 16:1182). (See Waterman
MS, Joyce J, Eggert M 1991 Phylogenetic Analysis
of DNA Sequences, pp 5989; Miyamoto MM,
Cracraft J eds. Oxford University Press, New York;
DNA sequence information, databases, indel
scanning: http://indelscan.genomics.sinica.edu.tw/
IndelScan/.
Independence: Two events are independent when the
occurrence of one does not affect the chance of
occurrence of the other. Genes at a distance of 50 map
units or more segregate independently, the sex of the
first child is (normally) independent of the sex of
the next one, if two pennies are tossed they can land
on their head or their tail independently from each
other unless they are defective or biased.
Independence Test: association test (contingency chi
square).
Independent Assortment: Alleles of different loci (non-
allelic genes) may re-assort freely in the gametes and
therefore segregate independently in zygotes in the
absence of a linkage. The independent assortment of
alleles is one of the most essential discoveries of
Mendel and it is frequently called Mendels third law.
Mendelian laws
Independent Events: These events do not affect or
influence each other.
Indeterminate Inflorescence (raceme): The main axis
can elongate indefinitely but the branches terminate
in a flower bud. raceme
Index: Refers to an alphabetical or other ordered set of
files or symbols or numbers distinguishing particular
things in an array. For example: allele a
1
, 1
distinguishes this allele among all other a alleles, or
NK3 homeobox 3 of Drosophila or adp
fs
an adipose
allele conveying female sterility, or the second
asymmetric leaf locus as
2
(AS-2) of Arabidopsis.
Index Case: proband (propositus, proposita).
Index Locus: polymorphism information content
(PIC)
Index Value: This is a concept used for selection in
animal breeding. A score weights each trait and these
scores are summed in an index value. The use of
this index acts as a safeguard against the possibility
of selecting one particular trait only and thus
jeopardizing the overall success of the program
because disease susceptibility or low fertility, etc.
frequently accompany high performance. gain,
selection; Falconer DS 1960 Introduction to
Quantitative Genetics, Ronald, New York.
Indexers: This is an amplification system for specific
DNA fragments from whole genome digests without
the need for cloning. It uses restriction enzymes
class-IIs. The non-identical cohesive ends can be
selectively modified by ligation to synthetic oligo-
deoxy-ribonucleotides with the corresponding com-
plementary ends. This permits the introduction of
PCR and sequencing primer sites and labels into
small fragments of the genomic digest. An advantage
over cloning is that fragment losses, rearrangements
can be avoided without cloning, probes or libraries.
The procedure is applicable to small prokaryotic and
large eukaryotic genomes for analyzing sequence
tagged sites, restriction mapping, RFLP, sequencing
and DNA diagnostics. restriction enzymes class-
IIs, PCR, sequence tagged site; RFLP; Unrau P,
Deugau KV 1994 Gene 145:163; Guilfoyle RA et al
1997 Nucleic Acids Res 25:1854; SibsonDR, Gibbs
FEM 2001 Nucleic Acids Res 29(19):e95.
Indians: Native Americans
Indicator Mice: This is transgenic for a recombinase
(Cre or Flp). When it is crossed to another transgenic
line carrying a construct with a FRTsequence in front
of the structural gene LacZ, on Xgal medium
develops blue color only when the recombinase
flipped out the FRTstop codon. The test indicates the
functionality of the recombinase and its utility for
targeting. targeting genes, Cre/LoxP, Flp/FRT,
Xgal
Indirect Diagnosis: Denotes identification of a gene by
linkage rather than by direct evidence.
Indirect End-Labeling: Determines the distance of a
DNase hypersensitive site from a restriction enzyme
cleavage site. The chromatin is first digested by a
Klenow fragment of DNAase I and then it is isolated
and treated with a restriction endonuclease. The
double digest is subsequently separated by electro-
phoresis and probed with a sequence adjacent to the
restriction site. The size of the fragment generated by
the double cuts indicates the distance of the DNAase
hypersensitive site from the site of restriction. This
procedure can localize in the DNA the sites where
transcription may be initiated because hypersensitive
sites are correlated with the position of transcrip-
tionally active genes. DNase hypersensitive site,
Klenow fragment, restriction endonuclease; Li S
et al Methods 2000 22(2):170.
Indirect End-Labeling 991
I
Indirect Suppression: Some suppressor mutations
do not correct the primary change in the gene rather
they modify the translation process and thereby
suppress the expression of the mutation. suppressor
mutation
Indole: This is a heterocyclic compound present in
many organic associations in biological materials (see
Fig. I23). When excited by ultraviolet light, it
displays a characteristic fluorescence spectrum that
facilitates its rapid detection. Among other roles it is a
precursor of tryptophan synthesis: anthranylate
indole + serine tryptophan.
H
N
Figure I23. Indole
Indole Acetic Acid (IAA): This is a plant hormone
synthesized fromtryptophan via the pathway Trpin-
dole-3-acetaldoximeindole acetonitrile IAA or
Trp indolepyruvic acidindole-3-acetaldehy-
deIAA. (See formula at IAA).
Indophenoloxidase: See under the new name super-
oxide oxidase
Induced Fit: This fit of enzymes (proteins, ribozymes)
occurs when the conformation is so modified that the
activity improves; this may be caused by binding to a
ligand or substrate. Both the substrate and ligand may
change conformation for the fit. The crystal structure
of the encounter complex on the pathway of ligand
binding by IgE antibody SPE7 is formed by a wide
range of ligands that initially bind with identical
affinity. Non-specific ligands rapidly dissociate,
whereupon the antibody isomerizes to a nonbinding
isomer. Specific ligand complexes, however, slowly
isomerize to give a high-affinity complex (James LC,
Tawfik DS 2005 Proc Natl Acad Sci USA
102:12730). ligand, key-lock, DNA binding
proteins, Lac operon
Induced Helical Fork: After the binding protein contacts
a few bases of the DNA, it keeps apart the double
helix. Watson and Crick model, binding proteins
Induced Mutation: This is obtained by exposure to a
mutagen and is presumably generated by the mutagen
itself rather than by an incidental spontaneous event.
spontaneous mutation, mutation
Induced Replisome Reactivation: replication-restart
Inducer: A substrate or an analog of a substrate of an
enzyme prevents a repressor protein fromattaching to
the promoter (operator) of a gene and thus facilitates
its expression. induction, gratuitous inducer,
repression, activator proteins, inducible gene
expression
Inducible Enzyme: The presence of a substrate or a
substrate analog is required for their synthesis. Lac
operon, Ara operon; Monod J, Audureau A 1946
Ann Inst Pasteur 72:868.
Inducible Gene Expression: This is required in many
instances to stimulate the expression of a particular
gene (transgene) in a specific tissue or cells. Inducible
promoters are useful tools in biotechnology as they
can be employed for turning on/off genes in response
to special, physiological or developmental factors.
metallothionein, transcriptional activators, tran-
sactivator, VP16, two-hybrid hybrid method,
split-hybrid system, three-hybrid system, tetra-
cycline
Induction: This term has several meanings. Phage
induction refers to the facilitation of the transition
from the prophage stage to the lytic phase. The
induction of enzymes set into motion the catalytic
activity. The assembly of the pre-initiation complex
of transcription induces gene expression. Embryonic
development is induced by the transmission of
various exogenous and endogenous signals. In
reciprocal induction in development an inducer
may be positively affected by the tissue that is formed
by its inducing action. prophage, enzyme induc-
tion, regulation of gene activity, transcription,
signal transduction morphogenesis in Drosophila,
organizer, photomorphogenesis
Induction, Developmental: The fate of a cell or tissue is
affected by the interaction of the embryonic cell or
tissue with its neighbors. embryonic induction
Induction of a Lysogenic Bacterium: This is the process
of liberating phage particles by first inducing a
change from a prophage to a vegetative state of the
phage. zygotic induction, prophage
Induction of an Enzyme: This initiates the synthesis of
new enzyme molecules by the presence of an inducer
that may be the substrate or an analog of the substrate
of that enzyme. derepression, gratuitous inducer
Indusium: This is a membrane-type layer over the sorus
(sporangial cluster) of ferns.
Industrial Melanism: As industrialization (coal-burning
pollution) advanced (in Britain) the dark variants
(dominant) of the black peppered moth (Biston
betularia) increased as a selective trend to camou-
flage the insect on soot covered tree barks. natural
selection, adaptation; Biston betularia; Kettlewell
HBD 1961 Annu Rev Entomol 6:245.
992 Indirect Suppression
I
Infantile Amaurotic Idiocy: Tay-Sachs disease
Infarction: Refers to blood vessel necrosis caused by
coagulation (thrombus) obstructing proper circula-
tion. necrosis, thrombosis
Infection: Denotes invasion of a host by a virus or
another organism. The invader may establish a
mutually beneficial or neutral relation with the host
(symbiosis). Many bacterial species regularly inhabit
the host without causing any harm. In the infected
host different sets of host genes are either activated or
repressed than in the uninfected controls (Falkow S
2006 Cell 124:699). Infection by some bacteria
frequently results in pathogenic consequences. The
microbial agent generally subverts the host defense
system on the surface and adheres to the special
receptors. They engage the cytoskeleton to facilitate
penetration and disable the phagocytotic mechanisms
of the host cell. In order to maintain itself the infective
agent must overcome the immune system of the host.
After the invasion the pathogen may redirect the host
metabolism to its own interest and produces disease
symptoms. If the host quickly succumbs to the
disease a frequency-dependent selection may eventu-
ally work against the invader or over time the host
may develop resistance. In Listeria the transcription
of the virulence factor is controlled by the activator
PrfA that is thermoregulated by a 5 secondary
structure of Prfa. It blocks its ribosome binding at a
temperature below (37C) that of the host (Johansson
J et al 2002 Cell 110:541).
In latent infection the virus remains in a few copies
and a few viral proteins are expressed so that the host
defense is not evoked temporarily. At an opportune
moment the virus may enter a lytic stage. In chronic
infection the pathogen invades the host repeatedly or
the infection persists for a prolonged period. Latent
agents cause opportunistic infection when the
immune system is compromised.
For epidemic spread the basic reproductive number,
R
0
is used to define the mean number of infections
caused by an infected individual in a susceptible
population. However, there are large individual
differences in the infectiousness and several mathe-
matical procedures have been developed for the
prediction of disease spread (Lloyd-Smith JO et al
2005 Nature [Lond] 438:355). hostpathogen rela-
tionship, epidemiology, frequency-dependent se-
lection; Knodler LA et al 2001 Nature Rev Mol Cell
Biol 2:578; Hill AVS 2001 Annu Rev Genomics Hum
Genet 2:373; Kazmierczak BI et al 2001 Annu Rev
Microbiol 55:407; Gruenheid S, Finlay BB2003 Nature
[Lond] 422:775; virus entry into animal cell: Smith AE,
Helenius A 2004 Science 304:237; bacterial invasion:
Cossart P, Sansonetti PJ 2004 Science 304:242;
bacterial invasion machinery: Pizarro-Cerd J,
Cossart P 2006 Cell 124:715; parasite invasion:
Sibley LD 2004 Science 304:248; reviews of viral
infection mechanisms: Marsh MS Helenius A 2006
Cell 124:729; Greber UF, Way M 2006 Cell 124:741.
Infectious Center: This is a spot from where infectious
phage or bacteria can be produced.
Infectious Diseases: These diseases are not hereditary as
was assumed before the emergence of genetics yet
susceptibility may be genetically determined. Infec-
tious agents, however, undergo evolutionary changes
and new diseases emerge and re-emerge. They are the
major cause of human mortality worldwide. In 2002,
57 million deaths were caused by infectious agents,
especially among people under age of 50 years. Three-
quarters of the infections emerge from animals and
adapt to humans by new mutations. Pathogens acquire
the means to evade the human immune system and
develop resistance to antibiotics, medication and
vaccines. hostpathogen relation, matrix diseases;
Cooke GS, Hill AV 2001 Nature Rev Genet 2:967;
Morens DMet al 2004 Nature [Lond] 430:242; Merrell
DS, Falkow S 2004 Nature [Lond] 430:250; Boes M,
Ploegh HL 2004 Nature [Lond] 430:264; host and
pathogen models of plants and animals: Pradekl E,
Ewbank JJ 2004 Annu Rev Genet 38:347; http://
databases.biomedcentral.com/browsesubject/?sub_
id=2011.
Infectious Drug Resistance: Drug-resistant genes are
carried on the conjugative plasmids of bacteria.
conjugation bacterial, plasmid
Infectious Heredity: symbionts hereditary, Wolba-
chia, segregation distorter, plasmid, prions
Infectious Nucleic Acid: This may be a purified viral
DNA or RNA that may propagate in the host cell and
code subsequently for viral particles.
Infectious Protein: prion, encephalopathies, kuru
Inference, Statistical: Refers to conclusion(s) drawn
about a population on the basis of a randomsample of
the population. The conclusions are generally based
on statistical tests such as significance and likelihood.
Inference in general means reasoning; prediction of
an unknown on the basis of known or assumed facts.
significance level, confidence intervals, likeli-
hood, Bayes theorem, Bernoulli process
Infertility: This may be due to various causes such as
anatomical abnormalities of the sexual organs (her-
maphroditism, dysgenesis, testicular feminization
and polycystic ovary disease). Infectious diseases,
hormonal abnormalities, malfunction of CREM,
psychological factors, organic diseases, medications,
alcoholism or other substance abuse, malnutrition
and chromosomal defects (trisomy, translocations,
Infertility 993
I
inversions, deletion, duplications and aneuploidy)
may also lead to infertility. Hereditary abnormalities
(cystic fibrosis, mental retardation, Kallmans syn-
drome, Kartagener syndrome and myotonic dystro-
phy) may involve infertility. In the US nearly 15% of
couples are involuntarily infertile. In about 2050%
of human infertility cases males are involved; 70
90% of them have defects in spermatogenesis or
spermiogenesis. After the age of 50, semen volume
and sperm concentration gradually decrease (in some
cases increase), spermmotility is reduced and fertility
rate is lower. Male infertility may be due to the
absence of a 10 repeat CAG microsatellite within the
mitochondrial DNA polymerase gene (Rovio AT
et al 2001 Nature Genet 29:261).
Spermatozoa with large heads, a variable number
of tails and an increased chromosome number is a
common cause of sterility in men. A genome-wide
microsatellite scan of 10 infertile men with this
phenotype revealed that they were homozygous for
single nucleotide deletion in a common region
harboring the aurora kinase C gene (AURKC,
19q13.3). This founder mutation results in premature
termination of translation, yielding a truncated
protein that lacks the kinase domain (Dietrich K
et al 2007 Nature Genet 39:661).
About 38% women may be infertile. The con-
sequences of the long-term use of fertility drugs on
the incidence of ovarian cancer may not be entirely
clear (Parazzini F et al 2001 Hum Repr 16:1372).
Women who smoke have an early menopause that
may be due to exposure to the polycyclic aromatic
hydrocarbons (PAH) in the smoke. PAH binds to its
receptor (AHR) in the promoter of the BAX gene and
promotes apoptosis of the egg, leading to infertility
(Matikainen T et al 2001 Nature Genet 28:355). By
tissue transplantation between two sterile male mouse
lines, fertility may be restored because of comple-
mentation. fertility, fertilization, sex hormones,
ART, fecundity, gametogenesis, spermiogen-
esis, PN-1, sterility, azoospermia, cell cycle,
CBAVD, CREM, asthenozoospermia, smok-
ing, claudin-11, miscarriage, microsatellite, and
the other entries; Aurora Ogawa T et al 2000 Nature
Med 6:29; Moore FL, Reijo-Pera RA 2000 Am J
Hum Genet 67:543; Kidd S et al 2001 Fertility &
Sterility 25:237; Cooke HJ, Saunders PTK 2002
Nature Rev Genet 3:790.
Infiltration: This means the introduction of various
substances into the biological tissues by diffusion,
frequently facilitated by evacuation (under negative
pressure).
Infinite Allele Mutation Model (IAM): Among the
practically infinite number of genetic variations of
nucleotide sequences each mutation creates a new
allele that did not exist earlier in the genome. It
predicts that evolutionary alterations in (microsatel-
lite) DNA occur either by addition or deletion of one
copy (of tandem repeats) in a novel fashion.
stepwise mutation model, microsatellite; Kimura
M, Crow JF 1964 Genetics 49:725.
Infinitesimal Model: When a linkage is sought between
quantitative trait loci (QTL) and other genetic
markers, the analysis is conducted on the basis of a
null hypothesis that a particular chromosome or
chromosome segment segregates independently
from a QTL. QTL, interval mapping, null
hypothesis, adaptation
Inflammasome: This is a protein complex activating
inflammation reactions (Mariathasan S et al 2004
Nature [Lond] 430:213). Essential components of the
complex in response to bacterial RNA are cryopyrin
(encoded by the CIASI/NALP3 gene, 1q44), cas-
pases-1 (a cysteine protease [ASC] encoded at
11q22.2-q22.3), interleukin-1 [IL-1, 2q14] and
IL-18 [11q22.2-q22.3], Toll-like receptor [4q32] and
ATP. Caspase-1 activation promotes cell survival in
case of infection by bacteria, which produce pores on
the cell wall with the aid of secreted toxins (Gurcel L
et al 2006 Cell 126:1135). Macrophages deficient in
cryopyrin can activate caspases-1 and secrete IL-1
and IL-18 when infected with gram-negative Salmo-
nella typhimurium and Francisella tularensis.
Macrophages exposed to gram-negative Staphylo-
coccus aureus and Listeria monocytogenes require
both cryopyrin and ASC to secrete IL-1 (Mariatha-
san S et al 2006 Nature [Lond] 440:228; Kanneganti
T-D et al 2006 Nature [Lond] 440:233). caspases,
IL-1, IL-18, Toll, macrophage, gram nega-
tive, Salmonella, tularemia, Listeria, Staphy-
lococcus, Muckle-Wells syndrome, gout,
minireview: Ogura Yet al 2006 Cell 126:659.
Inflammation: This is a physiological response to
infection by pathogens or to adverse environmental
chemical or physical agents. Immunoglobulin G
(IgG) mediates proinflammatory responses. Sialyla-
tion of the Fc (fragment crystalline) of IgG switches
the response to an anti-inflammatory mode (Kaneko
Y et al 2006 Science 313:670). Despite being an
initial healing response, inflammation may eventual-
ly lead to a chronic state such as observed in
autoimmune diseases and cancer. In nearly 20%
of sporadic cancer inflammation plays a role and
NF-B promotes it (Pokarsky E et al 2004 Nature
[Lond] 431:461). Soluble epoxide hydrolase inhibi-
tors (e.g., AUDA-BE = 12-(adamantan-1-yl-ureido)-
dodecanoic butylester) (see Fig. I24) reduce
lipopolysaccharide-induced mortality, systemic
hypotension and tissue injuries without any adverse
994 Infiltration
I
side effects (Schmelzer KR et al 2005 Proc Natl Acad
Sci USA102:9772). Systemic inflammatory response
is a life threatening condition caused by an increase of
proinflammatory cytokines such as IL-1 and TNF-
(without microbial infection). Toll-like receptors are
involved in gene-specific chromatin modifications
and are associated with transient silencing of one
class of genes, which includes proinflammatory
mediators, and priming of the second class, which
includes antimicrobial effectors (Foster SL et al 2007
Nature [Lond] 447:972). NF-B, cancer, nitric
oxide, cyclooxygenase, immunoglobulins, an-
tibody, Toll, sialic acid; Nature [Lond] 420:846
891[2002]; http://pstiing.licr.org/.
N
H
N
O
O O
H
Figure I24. AUDA-BE
Inflammatory Bowel Disease: Crohn disease, ulcer-
ative colitis; review: Xavier RJ, Podolsky DK 2007
Nature [Lond] 448:427.
Inflorescence: This is a cluster of flowers, characteristic
for the taxonomic classification of plants. Inflores-
cence branching in maize is under the control of
trehalose enzymes (see Fig. I25) (Satoh-Nagasawa N
et al 2006 Nature [Lond] 441:227). trehalose;
Vollbrecht E et al 2005 Nature [Lond] 436:1119;
evolution of inflorescence: Prusinkiewicz P et al 2007
Science 316:1452.
Monocot
Dicot
Figure I25. Inflorescences
Influenza Virus: This is a group of commonly spherical
(120-nm) single-stranded RNA (1290014600-nu-
cleotides) viruses. The genome of the A strain is
segmented and consists of eight molecules, a central
one surrounded by seven others. When its density
becomes high, defective interfering particles, con-
taining deletions, may slow down viral multiplication
(see Figs. I26 and I27).
Figure I26. Influenza
Neuraminidase
Hemagglutenin
Matrix protein RNA
Lipid
Matrix protein
Figure I27. Structure of the influenza virus
Their major surface glycoprotein is hemagglutinin
(560 amino acids), which is usually modified by
mutation (Plotkin JB, Dushoff J 2003 Proc Natl Acad
Sci USA 100:7152). Hemagglutinin, after cleavage
by the host proteases, mediates the attachment of the
virus to the cell and the transfer of the ribonucleopro-
tein into the cell. The other common surface
glycoprotein is neuraminidase (460 amino acids)
which is anchored to the lipid membrane by its amino
end. The virus is classified/typed into subtypes
according to the hemagglutinin (H) and neuroamini-
dase (N). In humans, H1N1, H2N2, H3N2 and H5N1
subtypes were so far commonly responsible for
epidemics. The H5N1 virus caused the bird influenza
outbreak in Vietnam in 20032004. The transmission
of the avian virus from birds to pigs and humans has
been verified but no human to human transmission
has been found although the potential human-to-
human infection is possible (Hien TTet al 2004 New
England J Med 350:1179) (see Fig. I28). Mouse is
infected with the influenza virus but it is not a suitable
model for the study of transmission. Guinea pigs can
spread the virus by droplets to other animals (Lowen
AC et al 2006 Proc Natl Acad Sci USA 103:9988).
The avian and the human strains differ in the
anatomical distribution of the preferred binding
molecules sialic acid linked to galactose: SA2,3Gal
and SA2,6Gal. The latter is dominant on the
epithelial cells in the nasal mucosa but SA2,3Gal
is rare there. In the paranasal sinus epithelium,
pharynx and bronchi mostly express SA2,6Gal. The
human-derived H5N1 recognizes preferentially
SA2,6Gal bound extensively to bronchial epithe-
lium and less to alveolar cells. In contrast avian
Influenza Virus 995
I
viruses bind extensively to alveolar SA2,3Gal. This
difference may be the basis of the relatively
inefficient human-to-human transmission of H5N1
(Shinya. K. et al. 2006 Nature [Lond] 440:435).
Hemagglutinin receptor mutations at amino acids 182
and 192 independently convert hemagglutinin of
H5N1, the avian virus into the human-recognizing
form and the human form still recognizes the avian
host (Yamada S et al 2006 Nature [Lond] 444:378).
Two amino acid changes in the HA receptor may
abolish transmission in ferrets (Tumpey TM et al
2007 Science 315:655).
The H7 type is extremely pathogenic to poultry and
can jump over to humans (Webby RJ, Webster RG
2003 Science 302:1510). Equine influenza virus
(H3N8) can jump to dogs (Crawford PC et al 2005
Science 310:482). Migratory birds may pose a great
risk for the rapid spread of diseases. The evolution of
the virus depends primarily on the antigenic varia-
tions. That is not exactly the same as the nucleotide
replacements in the genetic material because some of
the mutations do not involve amino acid replacements
and some amino acids have disproportionately large
antigenic effects (Smith DJ et al 2004 Science
305:371). All the major human influenza pandemics
seem to have originated by mutation from avian
viruses (Taubenberger JK et al 2005 Nature [Lond]
437:889). The reconstructed virus causing the lethal
worldwide epidemic of 1918 owed its virulence
compared to the current influenza viruses (H1N1) to
a few mutations, its ability to replicate in the absence
of trypsin, caused death in mice and embryonated
chicken eggs and increased growth in human
bronchial epithelial cells. The RNA for the 8 viral
genes were preserved and isolated from in formalin
fixed lung autopsy samples and from unfixed, frozen
samples of a corpse buried in permafrost in 1918
(Tumpey TM et al 2005 Science 310:77).
The C type flu virus has another single surface
glycoprotein, HEF that destroys the cellular receptor
by neuraminate-O-acetylesterase. The viral M1 pro-
tein (M
r
28K) controls the nuclear traffic of the
virus. The virus has several types, designated by place
of origin such as Spanish, Hong Kong and Russian
strains or as Type A (most common and reoccurring
in 23 year cycles), Type B (causes epidemics in 45
year cycles),and Type C (a sporadically occurring
one). In Type Avirus the hemagglutinin HA1 plays an
important role for infectivity. The nucleotide substi-
tution in this domain is high (5.7 10
3
per site). At
least 18 amino acids are critical for evading the host
immune response. The expected mutation rate at
these sites has predictive value for the pharmaceutical
industry for the production of inoculation for the
following year. The Spanish Flu of 1918 was
particularly devastating as it killed 675,000 Amer-
icans and reduced the average life expectancy by 10
years. Influenza virus A encodes and translates, by
an alternative reading frame, an 81-residue protein
PB1-F2, which promotes apoptosis. It appears that
upon infection this mitochondrially-localized protein
kills the host immune cells (Chen Wet al 2001 Nature
Med 7:1306). Birds, horses, swines and cats also have
influenza-type infections by different viruses.
The bird influenza virus posed a threat to human
populations only in 1997. The highly virulent flu
strains usually develop from reassorted viruses of the
human and avian types sometimes via the pig flu
virus. The nucleotide sequences of 169 H5N1 strains,
including 2,196 genes, have been reported (Obenauer
JC et al 2006 Science 311:1576). The avian flu
spreads to various species of birds, including
migratory birds, which may carry it to long distances,
and it infects humans but at present time (by 2008)
there is no firm evidence that infected humans would
transmit this avian virus to other human beings.
Swans are particularly susceptible to H5N1 and
among the domestic poultry ducks are probably less
susceptible than chickens. Viral infection of the
respiratory tract occurs with possible secondary
infection by Streptococcus, Staphylococcus and
Haemophilus bacteria. Vaccination against the influ-
enza virus may be effective. However, there are
problems because of the annual variations in the
subtypes and the best methods of manufacturing
effective vaccines against the variations in the
prevailing types. Also, a few unprotected individual
birds can reignite the epidemics (Saville NJ et al 2006
Nature [Lond] 442:757). Because of the frequent
variations the industry must produce a new type of
vaccine every year that provides limited protection
when the virus changes. Amino acid changes in
hemagglutinin by converting at site Serine 223 to
Asparagine improved the hemagglutinin titer and
effectiveness of the H5N1 vaccine (Hoffmann E.
et al. 2005 Proc. Natl. Acad. Sci. USA 102:12915).
The prevention of virus transmission is of major
importance. Targeted prophylaxis, quarantine and
Figure I28. Peking duck source of the famous roast
and flu
996 Influenza Virus
I
pre-vaccination may effectively contain a pandemic
(Longini IM et al 2005 Science 209:1083). Several
vaccines may elicit adverse reactions in some
individuals because of host genetic factors. Antiviral
drugs have not been widely exploited. Neuraminidase
inhibitors such as Zanamivir, Ralenza, Oseltamivir
and Tamiflu may restrict all types of influenza viruses
(Laver G 2005 Nature [Lond] 434;821; Matrosovich
MN et al 2004 J Virol 78:12665). These drugs are
effective in prevention and generally do not have any
serious side effects except in cases of cirrhosis of the
liver or poor general health (Kaji Met al 2005 J Infect
Chemother 11:41). Recent findings have revealed
around 10% increase in psychoneurotic side effects
following the use of Tamiflu in Japan. Mutation to
Oseltamivir had been observed in humans (Mai Le Q
et al 2005 Nature [Lond] 437:1108; Moscona A 2005
New England J Med 353:2633). X-ray crystallogra-
phy has revealed a cavity adjacent to the active site of
neuramidinase 1 that closes on ligand binding. This
observation has brought to light a new potential target
for antiviral drug development (Russell RJ et al 2006
Nature [Lond] 433:45). reassortant, hemaggluti-
nin, neuraminidase deficiency, Newcastle virus,
prophylaxis, quarantine; Gibbs MJ et al 2001
Science 293:1842; Bae S-Het al 2001 Proc Natl Acad
Sci USA 98:10602; Steinhauer DA, Skehel JJ 2002
Annu Rev Genet 36:305; Ferguson NM et al 2003
Nature [Lond] 422:428; Palese P 2004 Nature
Medicine 10:S82; large-scale sequence variation in
the human A virus: Ghedin E et al 2005 Nature
[Lond] 437:1162; Fauci AS 2006 Cell 124:665;
evolution of influenza virus: Nelson MI, Holmes EC
2007 Nature Rev Genet 8:196; Influenza virus
problems: Science 2006 312:379; influenza virus
resource: http://www.ncbi.nlm.nih.gov/genomes/
FLU/FLU.html; http://influenza.genomics.org.cn; vi-
rus A genotyping: http://www.flugenome.org/, anno-
tation of virus Aand B: http://www.ncbi.nlm.nih.gov/
genomes/FLU/Database/annotation.cgi.
Informatics: This is a systemof databases and electronic
retrieval. bioinformatics, databases
Information: It is obvious that the more the information
that is available about a population the easier and more
reliable is the decisionof the geneticist about a parameter
of that population(s). Statistically, the information I
p

1
Vp
indicating that the total amount of information is
inversely proportional to the variance (V) of the statistic
employed. The calculation of the information for a
particular set of data can be carried out by:
I

1
m
dm
d
_ _
2
_ _
where mis the expectationinterms of parameter , and
is the sum of all classes. R.A. Fisher pointed out that
maximizingthe likelihoodfunctionprovides anestimate
of T, which has the limiting value of 1/nV
T
= I. The
reciprocal of the variance of the maximum likelihood
estimate permits assessing the value of other estimates.
If the variances obtained by other methods are not 1/nI,
they do not provide the complete possible information
and are therefore inferior to the maximum likelihood
statistics. maximum likelihood, variance; Mather K
1957 The Measurement of Linkage in Heredity,
Methuen, London.
Information (in statistics): It is sometimes called
support or lod-score. lod score
Information Retrieval: Refers to the procedures to
obtain information from a set of stored data, such as
a specific nucleotide sequence in the database.
databases; Yandell MD, Majoros WH 2002 Nature
Rev Genet 3:601.
Information Theory: http://www.lecb.ncifcrf.gov/
toms/paper/primer.
Informational Macromolecules: Denote DNA, RNA,
proteins that can convey genetic, developmental,
biochemical and evolutionary instructions to a cell or
organism.
Informative Mating: This reveals the inheritance or
linkage relationship of a gene or an allele.
Informativeness: Refers to the usefulness of a test for
making a distinction between/among alternative
hypotheses. robustness
Informed Consent: A genetic counselor may face a
dilemma regarding the information he/she may wish
to withhold from the counselee because of the
psychological impact. Legally, all the dangers
associated with the professional evaluation should
be shared with the individual, and within the legal
limits of confidentiality. Action to be pursued
requires informed consent. Organ donation for direct
use for human treatment involves different ethical
considerations and informed consent for organ
donation for medical or basic biological research.
Both may involve risk for the donor and in the latter
case (e.g., oocytes donation for stemcell research) the
beneficial effects for society may not be seen for years
or ever (Magnus, D. & Cho, M.K. 2005 Science
308:1747). counseling genetic, genetic privacy,
confidentiality, bioethics, gene therapy, can-
cer gene therapy, public opinion, morality,
biopiracy; US Office for Protection from Research
Risks (OPRR) 1993, Dept. of Health and Human
Services, Washington DC; Greely HT 2001 Annu
Rev Genet 35:785.
Informosome (masked RNP): Refers to mRNA com-
plexed with protein and thus having a very low
Informosome 997
I
turnover rate and stability. (Spirin AS 1994 Mol
Reprod Dev 38:107).
INGI: p53
ingi: hybrid dysgenesis, I-R
Ingression: This is the movement of cells from the
surface into the inner region. gastrulation
INH: A protein complex that contains at least six
species, isolated from oocytes. It inhibits the activa-
tion of pre-MPF. maturation protein factor
INHAT: Refers to an inhibitor of histone acetyltrans-
ferases CBP and PCAF. CBP, PCAF
Inherency: Genes that are important for organogenesis
in higher evolutionary forms usually have some
comparable representatives in more primitive forms.
Inheritance: This is the process of receiving genes from
ones ancestors and passing them on to ones
offspring. DNA codes these genes in eukaryotes
and prokaryotes; in some viruses the transmitted
genetic material is RNA. The genetic material may be
located in the nucleus (nuclear inheritance) or carried
by the nucleoid in prokaryotes. The genetic material
in mitochondria and chloroplasts mediates extranu-
clear inheritance. Prokaryotes and cytoplasmic orga-
nelles may also have plasmid vehicles of heredity.
Colloquially people may say that a certain trait of the
children is inherited from one or the other parent.
Actually, traits are not inherited, only the genes,
which determine them, are transmitted. Epigenetic
modification of histone proteins may, however
temporarily be maintained in the offspring. geno-
type, phenotype, heredity, genetics, reverse
genetics, DNA, RNA, prions, genealogy,
pedigree, acquired characters inheritance, epi-
genetics, dauermodification
Inheritance, Cortical: cortical inheritance
Inheritance, Cultural: This refers to information transfer
by non-biological means such as customs, traditions
and behavior. Cultural inheritance plays a significant
role in the phenotype but the genes of the organism
determine its genetic significance. The genes involved
may have different selective values. fitness
Inheritance, Delayed: delayed inheritance
Inhibin: This is an antagonist of activin. Inhibins
are glycoproteins (A and B) in the seminal and
follicular fluids and inhibit the production of follicle-
stimulating hormone and regulate gameto-genesis,
embryonic and fetal development as well as blood
formation (hematopoiesis). activin, FSH
Inhibition: inhibitor
Inhibition of Transcription: Any inhibitor of the RNA
polymerase protein can block transcription. Bis
([1,10]-phenanthroline) cuprous chelate ([OP]
2
Cu
+
)
is one such inhibitor. On its own it is not gene-
specific, however, it can cut oxidatively single-
stranded DNA templates and is suitable for mapping
transcription initiation sites (see Fig. I29). Gene-
specific inhibition of transcription can be accom-
plished by antisense RNA, triple-helix formation and
DNA-binding polyamides. Gene-specific inhibition
is feasible by targeting [OP]
2
Cu
+
) to the promoter in
an open transcription complex with the aid of
template-specific oligonucleotides with [OP]
2
Cu
+
attached to the oligonucleotides at various positions
at either ends or interstitially. The template strand
is then interrupted by the [OP]
2
Cu
+
position, e.g.,
OP-5-GUGGA-3, 5-GUGGA-3-OP or 5-GU[OP]
GGA-3. The inhibition is most efficient with 5
nucleotides representing one-half turn of A or B
DNA-type double helix. The preferred cleavage
site is 23 nucleotide from the OP linkage toward
the 3 end. 2-aminouridine appears to increase the
specificity of the intercalation. The presence of the
RNA polymerase is essential for the binding.
antisense RNA, TFO, triple helix formation,
polyamides, transcriptional repression, tran-
scription corepressor, RNAi, DNA types; Milne
L et al 2000 Proc Natl Acad Sci USA 97:3136.
RNA polymerase
N
O
N N
H
N
RNA
DNA
H
+Cu
5 T A A T G T G G A A T 3
G U G G A
T A C A C A C C T
2 1 +1
3 RNA oligonucleotide
5
Figure I29. Inhibition of transcription
998 INGI
I
Inhibitor: This is a substance that interferes with the
activity of an enzyme versus a repressor that prevents
the synthesis of the enzyme. regulation of enzyme
activity
INI1 (integrase interacting protein): This tethers the
retroviral (HIV) integrase enzyme and facilitates the
integration at or near the DNase hypersensitive site of
the eukaryotic chromosome. integrase, DNase
hypersensitive site, Cre/loxP, FLP, resolvase,
retroviruses, HIV
Initial Sequence Contig: Refers to the assembly of
overlapping sequences from a single clone.
Initiation Codon: This is the first translated codon. In
prokaryotes it is commonly AUG (90%) translated
into formylmethionine but GUG(8%) and UUG(1%)
can also be used. AUU is rarely employed because
IF3 discriminates against this non-canonical codon
versus the above three canonical codons. In prokar-
yotes the non-formyl AUG is prevented from
initiation by the secondary structure in the mRNA
and the interaction between mRNA and ribosomal
RNA. In eukaryotes AUG does not code for
formylmethionine but for methionine. In some rare
cases in mammals the initiation codon is CUG or
GUG (Tailor, C.S. et al. 2001 J. Biol. Chem.
276:27221, Schwab, S.R. et al. 2003 Science
301:1367). In some insect viruses the initiator codon
is CAA (glutamine) and an initiator tRNA is not
required. The initiation codon is charged to a specific
initiator tRNA. aminoacyl-tRNA synthetase,
elongation factors, Shine-Dalgarno sequence,
ribosome scanning, translation initiation, tran-
script elongation, modified bases, genetic code
Initiation Complex: This contains the small subunit of
the ribosome with associated mRNA, aminoacylated
tRNA and the various initiation protein factors and
energy donor nucleotide triphosphates. In prokar-
yotes the initiation complex, comprising three single
polypeptide chains proteins, has a mass of 150 kDa.
In eukaryotes about 10 initiation factors compris-
ing >25 polypeptide chains has an aggregate mass
of 1,200 kDa. Although both types of systems
require the ternary complex of Ifs (initiation factors)
GTPtRNA, several differences exist in the details
of executing the functions. In eukaryotes the ternary
complex usually binds the 40S ribosomal subunit
before the mRNA binding although the reverse
sequence of events is possible. In prokaryotes there
is a near equal chance of selection of either of these
possible routes of binding the 30S subunit. In
eukaryotes the 40S ribosomal subunit recruits to the
5 cap of the mRNA, the initiation factors eIF3 and
eIF2-GTP and the initiator tRNA. EIF3 then interacts
with the cap-binding complex eIF4F and the 40S
subunits scan for the appropriate start codon in the
mRNA. Factor eIF5 releases eIF2 and in the presence
of eIF5B-GTP both 40S and 60S ribosomal subunits
are assembled into the 80S ribosome. Then the
start codon Met-tRNA
1
instead of the ribosomal P
site eIF5B is released from GTP to proceed with
peptide extension. The Cricket Paralysis Virus can
initiate translation without this complete machinery
by the placement of the IRES (internal ribosomal
entry site) at the A site of the ribosome. Other insect
viruses, however, require most of the regular initia-
tion factors and Met-tRNA
1
(Jan, E. et al. 2003 Proc.
Natl. Acad. Sci. USA 100:15410). protein synthe-
sis, preinitiation complex, initiation factors;
Kimball SR 2001 Progr Mol Subcell Biol 26:155.
Initiation Factor for Transcription: initiation complex,
IF, eIF
Initiation Factors of Protein Synthesis: These are
involved in initiation of translation. eiF, IF and
iIF; Sonenberg N et al eds. 2000 Translational
Control of Gene Expression, Cold Spring Harbor
Lab. Press, Cold Spring Harbor, New York.
Initiator (Inr): promoter, core promoter
Initiator Codon: This is the starting site of translation in
the mRNA; it is generally 5-AUG-3 but sometimes it
can be 5-GAG-3, 5-GUG-3 or 5-GUA-3. pro-
tein synthesis, translation
Initiator tRNA: This carries formylmethionine (prokar-
yotes) and initiation methionine (eukaryotes) to the P
site of the ribosome to begin translation. The structure
of this tRNA can be distinguished from the rest of the
transfer RNAs. This rRNA in bacteria, besides the
AUG, may recognize GUG and UUG as a formyl-
methionine codon. Not all proteins begin with a
methionine because of processing. Mutation in the
anticodon of tRNA
fMet
may start translation with
amino acids other than formylmethionine or methio-
nine. The eIF2 initiation protein distinguishes
between the initiator and the elongation tRNA
Met
on the basis of several criteria: the A1:72 base pair at
the bottomof the amino acid acceptor stem, three G:C
pairs in the anticodon stem, initiators do not have the
TC in the Tarm and A54 rather than T54 is in the T
arm and within the T loop A60 replaces pyrimidine-
60. In plants and fungi, at position 64 a phosphor-
ibosyl group is attached to the 2-OH of the ribose.
Additional variations may exist in some species.
protein synthesis, ribosome, transfer RNA,
IRES, initiation codon, eIF2, pseudoknot;
OConnor M et al 2001 RNA 7:969.
Injectisome: This is an apparatus of pathogenic bacteria
for delivering type III secretions into the host (see
Fig. I30). The tip of a long injection needle of Yersinia
Injectisome 999
I
composed of several proteins is diagramed after
Mueller (Mueller CA et al 2005 Science 310:674).
Figure I30. Injecting needle tip
INK (p
INK
): Polypeptide inhibitors of cyclin-dependent
kinases involve and cause cell cycle G1 phase arrest.
The INK family includes proteins p15, p16, p18 and
p19 bind Cyclin D/CDK4. cancer, cell cycle,
CDK, p15, p16, p18, p19
Innate: This means inherited, congenital. congenital
Innate Immunity (natural immunity): This is based on
cell surface receptors (pattern recognition receptors,
PRR) and other protein molecules encoded by the
germline. The Toll-like receptors (TLR) through their
TLR/IL-1 receptor domains (TIR) recognize extra-
cellular or membrane-enclosed foreign organisms.
The NOD-like (nucleotide-binding oligomerization
proteins, NLR) include different families of proteins.
NOD1 and NOD2 recognize bacterial peptidogly-
cans. The NALP3 inflammasomes control proin-
flammatory cytokines IL-1 and IL-18. They respond
to PAMPs (pathogen-associated molecular pattern
recognition proteins) and DAMPs (danger-associated
molecular pattern). Viruses are recognized RIG-like
helicases. (See details of function reviewed by
Meylan E et al 2006 Nature [Lond] 442:39).
These systems generally recognize carbohydrate
structures and then stimulate the synthesis of various
molecules such cytokines, interleukins and tumor
necrosis factor. Some natural killer cells (neutrophils,
macrophages) recognize inimical cells by lectin-like
membrane receptors. This innate immunity is a rather
fixed, rigid system in comparison to the acquired
immunity mediated by immunoglobulins which are
greatly adaptable and variable. Innate immunity can
shape the development of the acquired immunity by
interacting with it. The protein fragments cut up by
the macrophages may be presented to the adaptive
immune system represented by the B and T cells. It
may guide the selection of antigens by lymphocytes
and the secretion of cytokines by the helper T
lymphocytes. Innate immunity is the first line of
defense by initiation of inflammation through recruit-
ing phagocytic and bactericidal neutrophils and
macrophages. The innate immune system recognizes
foreign bodies with the aid of pattern-recognition
receptors. In mouse double-strand RNA viruses
are recognized by retinoic-acid-inducible protein I
(RIG-I) and by the melanoma-differentiation-asso-
ciated gene 5 (MDA5) that encodes another antiviral
protein. RIG-I responds to dsRNA by the produc-
tion of interferon whereas MDA5 is specific for
polyinosinic-polycytidylic acid. RIG-I responds to
paramyxoviruses, influenza virus and Japanese
encephalitis virus. MDA5 is critical for picorna-
viruses (Kato H et al 2006 Nature [Lond] 441:101).
The complement is part of innate immunity but it
also cooperates with the acquired immunity system.
Innate immunity is also present in insects (Drosophi-
la) although they lack the adaptive immunity system
found in vertebrates. The innate defense system of
bacteria recognizes non-methylated DNAand cleaves
the foreign DNA by restriction endonucleases.
Mammals possess relatively few CG pairs and the
C is commonly methylated within the PuPuCGPyPy
sequence. The unmethylated bacterial, fungal and
insect CG pairs then activate macrophages, dendritic
and B cells without normally attacking the self-DNA.
Through the mediation of the MEK signal transduc-
tion pathway and NF-B the genes of the acquired
immune system are turned on. The specificity of the
discrimination is attributed to the different Toll-like
receptors, which recognize bacterial lipopolysacchar-
ides, glycolipids, flagellin, etc. Another signaling
route is through DNA-PK. These two pathways may
anastomose. The defense system in Drosophila relies
on phagocytosis, proteolytic cascades, melanin
formation, opsonization and the synthesis of anti-
microbial peptides. immune system, natural
antibody, complement, acquired immunity,
vaccine, lymphocytes, antibody, interferon,
opsonins, antimicrobial peptides, Toll, side-
rophore, flagellin, signal transduction, NF-B,
DNA-PK, CD14, hostpathogen relationship,
T-bet; Aderem A, Ulevitch RJ 2000 Nature [Lond]
407:782; Aderem A, Hume DA 2000 Cell 103:993;
Kimbrell DA, Beutler B 2001 Nature Rev Genet
2:256; Roger T et al 2001 Nature [Lond] 414:920;
Janeway CA Jr, Medzhitov R 2002 Annu Rev
Immunol 20:197; relationship between innate and
adaptive immunity: Hoebe K et al 2004 Nature
Immunol 5:971.
Innervation: Refers to the development of the nervous
system in an organ or tissue.
Innexins: These are invertebrate gap-junction proteins
which are functionally similar to connexins in
vertebrates. gap junction, connexins
INO80: This is a chromatin remodeling complex
participating in the DNA double-strand break repair.
(Morrison AJ et al 2004 Cell 119:767; DN repair).
1000 INK
I
Inoculum: Usually a small microbial cell sample is used
for starting a culture (see Fig. I31).
Figure I31. Inoculation loop
INOH: This is a biochemical pathway database (http://
www.inoh.org/).
Inorganic Pyrophosphatase: This cleaves off 2 mole-
cules of phosphates from molecules.
Inosine: hypoxanthine (see Fig. I32).
O
N
N
N
HN
HO
OH OH
O
Figure I32. Inosine
Inosinic Acid: hypoxanthine
Inositides: phosphoinositides
Inositol: This occurs in cells as myoinositol as part of
the vitamin B-complex. It is formed through cycliza-
tion from glucose-6-phosphate (see Fig. I33). It is an
indispensable constituent of some lipids (phosphoi-
nositides). In some forms of diabetes it may
accumulate in the urine. signal transduction,
diabetes
OH OH
OH
OH
OH
HO
Figure I33. Inositol
Inositol Trisphosphate: phosphoinositides
Inparalog: This is a gene(s) evolved through more
recent duplications. Gene comparisons between
species are identified by INPARANOID algorithm
(Remm, M. et al. 2001 J Mol Biol 314:1041).
paralogous loci, outparalog
In-Planta Transformation: transformation genetic
Input Trait: In genetic engineering of plants the goal of
research is to facilitate the culture of plants (e.g.,
increase resistance to herbicides, pathogens, para-
sites, cold, etc.). The output traits include higher
nutrient content, modified plant products (e.g., lipids,
fatty acids) manufacturing special proteins (e.g.,
antibodies) and synthesizing special industrial raw
materials (e.g., silk fibroin, plastics). genetic
engineering
Inr: promoter
INSDC (International Nucleotide Sequence Database
Collaboration): http://www.insdc.org/; XML
Insect Control, Genetic: genetic sterilization, holo-
centric chromosomes
Insect Control, Physiological: This uses chemicals as
well as biological agents such as viruses, bacteria,
fungi, protozoa and natural parasites. Chemicals
include alkylating agents (e.g., methyl bromide) that
alter the DNA, organophosphates and carbamates that
inhibit choline esterases and thus the nerve function,
nicotine and derivatives act similarly as acetylcholine
mimics. Arsenics inhibit glycolysis, cyanides poison
the respiratory system. DDT, pyrethrins activate
sodium channels, growth regulators may inhibit
chitin synthesis, hormone synthesis, etc. However,
the effectiveness of many compounds may be dimin-
ished over time because of mutation to resistance.
(Wimmer EA 2003 Nature Rev Genet 4:225;
biological insect control: http://www.ent.iastate.edu/
list/directory/108.
Insect Resistance in Plants: Some plant species contain
genes for insect tolerance and these are being
incorporated into plant breeding material by conven-
tional techniques. The most successful insect resis-
tance gene, the Bacillus thringiensis toxin gene, has
been transformed into several species of dicots and
provides almost complete defense when it is
expressed under the control of efficient promoters.
Pea plants transgenic for -amylase inhibitor 1 and
2 are protected from the pea weevil (Bruchus
pisorum). Al-1 causes larval mortality at the 1
st
and 2
nd
instar stages whereas Al-2 is responsible for
blocking the maturation of the larvae. Maize plants
defend themselves against the armyworm (Spodop-
tera exigua) caterpillars by releasing a sesquiterpene
and indole. These volatile compounds encoded by the
stc1 and Igl genes, attract parasitic wasps, which
deposit their eggs and eventually destroy the caterpil-
lars. Some of these volatile defense compounds (cis-
3-hexen-1-ol, linalool, cis--bergamotene) perform
multiple tasks, e.g., repel herbivorous invaders,
decrease their rate of oviposition and recruit their
natural predators (Schnee, C et al 2006 Proc. Natl.
Insect Resistance in Plants 1001
I
Acad. Sci. USA 103:1129). Another species of
fall armyworm (Spodoptera frugiperda) is perceived
by the cowpea (Vigna unguiculata). Upon attack
the insect secretes a disulfide-bridged peptide
(
+
ICDINGVCVDAS

) called inceptin, that promotes


ethylene production in the plant and triggers the
production of phytohormones salicylic acid and
jasmonic acid that have a defense function. Inceptins
are proteolytic fragments of the subunit of
chloroplast ATP synthase. Only insects that earlier
fed on cowpeas produce inceptin in sufficient
quantity to defend against the herbivore (Schmelz,
EAet al. 2006 Proc. Natl. Acad. Sci. USA103:8894).
Spidermite-infected plants may release terpenoids
(-ocimene) that may stimulate defense-related genes
in uninfected lima bean plants. Plants transgenic for the
cyanogenic glucoside, dhurrin (see Fig. I34) become
resistant to the flea beetle Phyllotreta nemorum. Host
plant specialization of pea aphids may be affected by
an endosymbiotic bacterium (Tsuchida, T. et al. 2004
Science303:1989). Arabidopsis plants transgenic for
sesqiterpene synthase targeted to the mitochondria use
cytochrome oxidase subunit IV (CoxIV)linalool/
nerolidol) synthase construct emitted nerolidol and
its derivative 4,8-dimethyl-1,3(E),7-nonatriene ([E]-
DMNT) against insects (see Fig. I35).
CH
2
OH
H
H
H
OH
O
O C
CN
OH
H
OH
HO
H
H
Figure I34. Dhurrin
OH
Nerolidal
(E)-DMNT
Figure I35. Insect resistance substances in plants
These compounds attract the carnivorous predatory
mites (Phytoseiulus persimilis) to the plants and
provide defense against herbivorous insects (Kappers
IF et al 2005 Science 309:2070). Maize (corn)
earworm (Helicoverpa zea) is a pest of maize and
several solanaceous plants (tomato, potato). The host
plants produce a carboxypeptidase inhibitor to
prevent the pest from feeding on the plant tissues
but the pest can adapt by producing an inhibitor-
resistant protease. The crystal structure of the H. zea
B-type metallocarboxypeptidase has been revealed
that has shed light on its properties (Bays A et al
2005 Proc Natl Acad Sci USA 102:16602). The -
subunit of SnRK1 (SNF-related kinase) protein
kinase, GAL83, transcripts rapidly down regulate
sugars in the leaves of tobacco upon attack by
herbivores and move them to the roots. This defense
increases the root reserves and prolongs life and
facilitates survival (Schwachtje J et al 2006 Proc Natl
Acad Sci USA 103:12935). Secreted proteins en-
coded by parasitism genes expressed in esophageal
gland cells mediate infection and parasitism of plants
by root knot nematodes. The ingestion of 16D10
dsRNA in vitro silenced the target parasitism gene in
root knot nematode and resulted in reduced infectivi-
ty in Arabidopsis (Huang Get al 2006 Proc Natl Acad
Sci USA 103:14302). Insect have chemosensors for
the detection of their animal or plant targets (van der
Goes van Naters W, Carlson JR 2006 Nature [Lond]
444:302). Bacillus thringiensis, chitin, wound
response, hostpathogen relations, selection
types, high-dose/refuge strategy, lotaustralin,
herbivore, jasmonic acid; De Moraes CM et al
2001 Nature [Lond] 410:577; Farmer EE 2001
Nature [Lond] 411:854; Palumbi SR 2001 Science
293:1786; Tattersall DBet al 2001 Science 293:1826;
Schriber JM 2001 Proc Natl Acad Sci USA
98:12328; Kessler A, Baldwin IT 2002 Annu Rev
Plant Biol 53:299; Kennedy GG 2003 Annu Rev
Entomol 48:51; insect genomes: Heckel DG 2002
Annu Rev Entomol 48:235; grasshopper elicitor:
Alborn HT et al 2007 Proc Natl Acad Sci USA
104:12976.
Insect Viruses: These viruses are of diverse types. The
enveloped Baculoviridae and the Poxviridae have
double-stranded DNA. The mosquito iridescent virus
has non-enveloped dsDNA. The genetic material of
the Parvoviridae is non-enveloped single-stranded
DNA. The Reoviridae carry non-enveloped double-
stranded RNA. The Flaviviridae are single-stranded,
enveloped RNAviruses. The Drosophila C virus is a
non-enveloped ssRNA virus. The Baculoviruses are
important for engineering genetic vectors. baculo-
viruses; Friesen PD, Miller LK 2001 p. 443 in
Fundamental Virology, Knipe DM, Howley PM eds.
Lippincott Williams & Wilkins, Philadelphia, PA.
Insecticide Decay: Insecticides, pesticides and herbi-
cides may decompose spontaneously in soil at differ-
ent rates; 1,2-dichloroethane in 72 years, paraoxon in
13 months, atrazine (herbicide) in 5 months and
aziridine (synonymethylenimine, carcinogen) in 52 h.
The nematocide 1,3-dichloropene is converted into
transchloro-3-chloroacrylic acid in 10,000 years at
25C. However, when it is exposed to the enzyme
3-chloroacrylate dehalogenase of Pseudomonas
1002 Insect Viruses
I
pavonaceae hydrolytic dechlorination proceeds
at a half-time of 0.18 s, an increase of about 10
12
(Horvat CM, Wolfenden R V 2005 Proc Natl Acad
Sci USA 102:16199)
Insecticide Resistance: Such resistance usually devel-
ops rapidly in various populations of pests as a
response to detoxification of the pesticides. In several
insects mutations in one (Cyp6g1) of the P-450
cytochrome genes (90 in Drosophila) is responsible
for resistance to DDT as well as other chemicals
(organophosphates, neonicotinoids, benzoylpheny-
lureas). In mosquitos amplification of the detoxifying
carboxylesterase may occur. Point mutations in the
genes encoding -aminobutyric acid-gated chloride
channel nerve membrane convey resistance to
cyclodienes. DDT, organophosphates, cholin-
esterase, pyrethrin, nicotine; Denholm I et al
2002 Science 297:2222.
Insemination by Donor (DI): This is a therapeutic
process to secure offspring in the case of male
infertility. In the USA, this method accounts for
30,000 birth/year. Generally, cryo-preserved semen
of sperm banks is utilized. To avoid potential
consanguinity and the transmission of hereditary
diseases it is advisable to limit the number of
inseminations to less than 10 per donor. If the donors
are genetically screened the incidence of genetic
abnormalities may decline from25%to about half of
that in the general population where DI is not used.
ART, sperm bank, in vitro fertilization; Kuller
JA et al 2001 Hum Reprod 16:1553.
Insert Restriction Site into Plasmid: In this process
the restriction endonuclease gene is amplified by the
PCR and then the plasmid is opened up by
the restriction enzyme. After the primers are removed
the target DNA is inserted into the plasmid and
ligated to circularize the plasmid.
Insertion Elements: DNA sequences generally shorter
than 2000 bases, which can insert into any part of a
genome transposons are common in all organisms
from prokaryotes to eukaryotes (see Table I4). Some
of the bacterial insertion elements have the following
characteristics.
They do not carry any genetic information beyond
that needed for insertion. Viruses can act as insertion
elements in cells. Insertion elements are the major
factors of spontaneous mutability. According to
some estimates, 515% of the spontaneous mutations
in bacteria are caused by IS elements. The presence of
IS1 may increase deletion frequency of the gal operon
30 to 2,000 times. IS elements also cause chromo-
somal rearrangements. Many IS elements have a large
number of potential target sites, others exhibit clear
preferences. The mechanism of transposition is either
dependent on replication and the new copy is
transposed or it simply involves a relocation of the
existing element. The movement of the IS elements is
affected by host genetic factors (DNA polymerase,
gyrase, histone-like proteins, dam methylase, DnaA
protein and proteins mediating recombination).
The presence of IS elements may alter not just
mutation, but also gene expression by their presence
in the control regions of genes. In Drosophila
melanogaster the average insertion density (average
number of large insertions/kb/chromosome) is about
0.004 and the average frequency of their movement is
0.023. Some of the historical insertions have been
modified and have become permanent regulatory
elements of the genes. hybrid dysgenesis, copia
elements, retroposons, Ti plasmids, LIN, Tn,
transposable elements, illegitimate recombina-
tion, Ty, pathogenicity islands, RNA insertion
element, DD(35)E, site-specific recombination,
Francisella; Chandler M, Mahillon J 2000 p. 306 in
Mobile DNA II, Craig N et al eds. American Society
of Microbiology Washington, DC; Mahillon J et al
1999 Res Microbiol 150:675; bacterial insertion
elements: http://www-is.biotoul.fr/.
Insertion Vectors: These have selectable marker(s) and
restriction enzyme site(s) on the vector and chromo-
some where the foreign DNA can be inserted. The
insertion involves a single reciprocal recombination
and may generate duplication because the insert has
homology to the target. However, the homology does
not have to be complete.
Insertional Inactivation: The insertion of any type of
DNA into an antibiotic resistance or other gene
may inactivate the function (e.g., becomes anti-
biotic sensitive) because of the disruption of the
genes continuity. insertional mutation, pBR322;
McClintock B 1951 Cold Spring Harbor Symp Quant
Biol 16:13; Koncz C et al 1992 Plant Mol Biol
20:963.
Table I4. A few insertion elements
Name Size
(bp)
Inverted Terminal
Repeats (bp)
Target
Duplication
IS1 768 18/23 (E. coli) 811
IS2 1,324 32/41 (E. coli) 5
IS3 1,258 29/40 (E. coli) 3
IS5 1,250 16 (E. coli) 4
IS10 1,329 17/22 (Tn10) 9
IS66 2,548 18/20 (Agro-
bacterium
tumefaciens)
8
Insertional Inactivation 1003
I
Insertional Mutation: The insertion of a transposable
genetic element within a gene disrupts its function
and as a consequence, leads to lethal effects or altered
functions (see Fig. I36). The insertion may modify the
expression of the target genes by overexpression,
suppression of the mutant phenotype or alter it.
It has been recently demonstrated that many of the
insertions do not lead to an observable change in the
expression of the genes or their effect is minimal and
only sequencing of the target loci reveals their
presence. Labeled probes for the insert can selectively
isolate the gene carrying the insertion. Although it
was initially believed that the insertions occur at
random sites, it has now been documented that the
target sites upstream of the promoters or other
locations where no essential functions are disrupted
are preferred.
Figure I36. Insertional mutation of Arabidopsis
knocked out the stem but fertility of the fruits is
retained. (Rdei, unpublished)
The target selection is mediated by integrase or
transposase functions. In some cases only DNA
elements are involved in the insertions but retro-
transposons sever the target DNA and the free 3-OH
end primes the reverse transcription of the template
RNA element and the DNA is then inserted.
Generally, there is no homology-dependent pairing
requisite for recombination except for the type 2
introns. The insertion also requires protein co-factors
such as IHF, HU, MuA and MuB (an ATP-dependent
activator of Mu phage protein MuB). The IS10/Tn10
bacterial and the TC1/TC3 Caenorhabditis elements
interact specifically with a target site consensus. TC
transposase recognizes and is inserted at TA dinucleo-
tides. In IS10 the interaction with the target catalyzes
the excision of the element from the original location.
Retroviral as well as some other elements preferen-
tially choose nucleosomal sites where the DNA is
bent. Tn7 preferentially inserted to a conserved
attachment site in E. coli, located outside the bound-
ary of the glmS gene (glucosaminephosphate isomer-
ase, map position 83). The yeast element Ty3 has high
specificity for the promoters of RNA pol III-
transcribed genes whereas Ty1 and Ty5 express less
stringent specificities (although not exclusively)
within the same region. Ty1 also prefers insertion
when transcription is (potentially) active whereas Ty5
selects transcriptionally inactive sequences. There-
fore, Ty1 is well suited for the induction of insertional
mutations. Transposition is generally targeted to sites
outside the transposon yet it may occur within the
elements and often results in its destruction but it may
lead to the evolution of a new element. The maize
transposable elements and the Drosophila P element
move preferentially to nearby sites although they may
jump to other chromosomes. Agrobacterial vectors
can also produce insertional mutations in plants. The
position of insertions can be defined by various
polymerase chain reaction techniques. By the use of
microarray hybridization insertion libraries can be
screened with the aid of capture PCR(MahalingamR,
Fedoroff N 2001 Proc Natl Acad Sci USA 58:7420)
and on the basis of homologies to expressed sequence
tags. insertion elements, transposons, scanning
insertion mutagenesis, GAMBIT, T-DNA, gene
isolation, REMI, MICER, integrase, trans-
posase, introns, IHF, HU, Tn7 Tn10,
Caenorhabditis, DNA bending, Ty, Ac-Ds,
hybrid dysgenesis, transposition immunity, Alu
family, LINE, EST, microarray hybridization,
capture PCR, gene therapy, cancer gene
therapy, Agrobacterium; Vidan S, Snider M 2001
Curr Opin Biotechn 12:96; insertion mutagenesis in
mouse: Carlson CM, Largaespada DA 2005 Nature
Rev Genet 6:568; TRIPLES.
Inside-Out-Signaling: Signals emanating from within
the cell control the affinity of ligands and the ligands
in turn affect the physiological processes in the cell
(outside-in signaling). signal transduction; ligand;
Takagi J et al 2002 Cell 110:599.
Insigs (insulin introduced gene): Refers to encoded
enzymes regulating cholesterol homeostasis by
stimulation through insulin. cholesterol, SREBP;
Le JN et al 2006 Proc Natl Acad Sci USA 103:4958.
Insomnia: fatal familial insomnia
InsP
2
(inositol-1,4-diphosphate): Phosphoinositides
(see Fig. I37).
1004 Insertional Mutation
I
HO
HO
HO
OH
OH
OH
OK
OK O
O
O
O
P
P
Figure I37. InsP
2
InsP
3
(inositol-1,4,5-trisphosphate): This is a global
signaling molecule which liberates Ca
2+
in the
cytoplasm. IP
3
, phosphoinositides (see Fig. I38).
HO
HO
KO
OK
OK
OK
OK
O
O
OK
O
O O
O
O
OH
P
P
P
Figure I38. InsP
3
Inspection Bias: This denotes a bias toward biological
interest.
Instability, Genetic: This is caused by high rate of
mutation, defects in genetic repair, recombination
among repeated sequences (trinucleotide repeats,
inverted repeats), palindromes, the presence of
transposable elements, illegitimate recombination
and double-strand breaks. Exonucleases may degrade
misaligned tandem repeats and thus favor DNA
stability (Feschenko VVet al 2003 Proc Nat Acad Sci
USA 100:1134). mutator genes, mutagens,
chromosome breakage, chromosomal aberration,
DNA repair, trinucleotide repeats, repeats
inverted, at-risk-motif, transposable element,
cancer, stress; Myung K et al 2001 Nature [Lond]
411:1073.
Instar: In this phase the insect larvae are between
the processes of molting (shedding the outer cover
layer). In Drosophila three moltings take place after
hatching and before pupation. The first and second
instars last for one day each, whereas the third
instar lasts for two days. Drosophila
Instincts: A variety of innate behavioral patterns that
develop without learning although learning may
reinforce them, e.g., motherly love, nursing, fearing
for life, conforming to some standards. behavior
genetics, ethics, ethology, aggression
Institutional Biosafety Committee: This committee must
approve genetic engineering projects in terms of
(1) the source of the DNA used, (2) the nature of the
inserted DNA, (3) the hosts and vectors contem-
plated, (4) the protein products expected, (5) the
nature of the containment facilities and compliance
with the regulations of the National Institutes of
Health. recombinant DNA, recombinant DNA
and biohazards
Instructive Signal: This is receptor-mediated and
involves a signal transduction cascade. signal
transduction
Insulator: DNAelement(s) of 0.5 to 3 kbp that prevent(s)
interactions between enhancers and the target promoter
but it (they) may/may not permit the expression of
stably integrated transgenes. The chicken hypersensi-
tive site 4 DNA is an insulator that protects X-linked
mouse gene from repression but not from X chromo-
some inactivation (Ciavatta D et al 2006 Proc Natl
Acad Sci USA 103:9958).
Transcriptional activators may suppress transgene
silencing as chromatin insulators (Sutter NB et al
2003 Proc Natl Acad Sci USA 100:1105). However,
they must be located between the enhancer and the
promoter to be able act. When there is a spacer DNA
between the enhancer and the promoter the structural
gene is expressed as illustrated by the light bulb
switched on. When the spacer is replaced by an
insulator element the expression of the structural gene
is markedly reduced or eliminated. The insulator may
affect the organization of the chromatin or it may act
as a regulator of transcription. Such elements are Fab-
7 and Fab-8 or the HMR and HML elements
controlling sex determination in yeast.
An insulator may prevent position effect. Insulators
may show some sort of position effect and two cis
insulators may facilitate transcription rather than
blocking it. The boundary between heterochromatin
and euchromatin reveals a distinct pattern of
methylation of histone H3. The gypsy retrotranspo-
son can serve as an insulator by the use of two zinc
finger proteins (Su[Hw) and Mod[mdg4]) as well as
the centrosomal protein CP190 (Pai C-Y et al 2004
Mol Cell 16:737). The TFIIIC transcription factor
complex recruited to tRNA genes (located in the
pericentric heterochromatin) checks heterochromatin
from spreading into the euchromatin. The same
transcription factor is also localized between diver-
gent promoters. The TFIIC complex seems to tether
Insulator 1005
I
heterochromatin to the nuclear periphery where
transcription is limited (Noma K-i et al 2006 Cell
125 859). promoter, enhancer, silencer,
boundary element, sex determination in yeast,
CTCF, position effect, enhancer competi-
tion, histones, epigenesis, transcription factors,
transcription factories, chromosome territories;
Sun F-L, Elgin SCR 1999 Cell 99:459; Bell A et al
1998 Cold Spring Harbor Symp Quant Biol 63:509;
Bell AC, Felsenfeld G 1999 Curr Opin Genet Dev
9:191; Bell AC et al 2001 Science 291:447; Noma
K-I et al 2001 Science 293:1150; Gerasimova TI,
Corces VG 2001 Annu Rev Genet 35:193; Oki M,
Kamakaka RT 2002 Current Opin Cell Biol 14:299;
West AG et al 2002 Genes Dev 16:271; mechanisms:
Gaszner M, Felsenfeld G 2006 Nature Rev Genet
7:703; chromatin insulators: Valenzuela L, Kamakaka
RT 2006 Annu Rev Genet 40:107; see Fig. I39.
E
N
H
A
N
C
E
R
I
N
S
U
L
A
T
O
R
E
N
H
A
N
C
E
R
P
R
O
M
O
T
E
R
P
R
O
M
O
T
E
R
S
R
T
U
C
T
U
R
G
E
ON
OFF
N
E
G
E
N
E
A
L
S
R
T
U
C
T
U
R
A
L
S
P
A
C
E
R
Figure I39. Insulator effect
Insulin: This is one of the most important peptide
hormones (MW 5,700) in the body and it is
synthesized in the pancreas. The pancreas is a large
gland behind the stomach. The islets of Langerhans
produce and secrete this hormone into the blood.
Insulin regulates glucose uptake into the muscles by
glucose transporters, and into the liver by glucoki-
nase. With the assistance of glycogen synthase,
glycogen is made in the muscles and the liver. The
breakdown of glycogen is mediated by the insulin-
regulated glycogen phosphorylase. Glycolysis and
acetyl coenzyme A synthesis is boosted by insulin
through the enzyme phosphofructokinase and the
pyruvate dehydrogenase complex. Fatty acid synthe-
sis in the liver is promoted by acetyl-CoA carboxyl-
ase and neutral fat (triaglycerol) is stimulated by
insulin with the aid of lipoprotein lipase. Insulin
deficiency leads to the hereditary diabetes mellitus.
Diabetes is a very complicated disease which is
controlled by several genes involved either in the
differentiation of the islets of Langerhans or at
various stages in the synthesis and regulation of the
hormones. About 5 to 10% of the population in
western countries suffers from one or another form
of this disease. Of these cases, however, only 1/10
is insulin-dependent. Insulin-dependent diabetes
(IDDM) is largely familial and occurs early in life.
The non-insulin-dependent form of the disease
(NIDdM) generally affects those who become
diabetic after the age of 40. The latter has a relatively
small hereditary component and it is most common
among obese individuals in the age group of 50 to 60
years. One of the most important clinical manifesta-
tions of the disease is hyperglycemia (excessive
amount of sugar in the blood), but there are many
other complex characteristics. Symptoms of diabetes
are manifested in nearly 60 known human diseases.
A well-controlled diet and a continuous supply of
insulin can effectively manage the early onset
diabetes. The treatment of the other forms (NIDDM)
varies according to the causative metabolic defect.
The primary structure of insulin was first deter-
mined by the two-time Nobel laureate, F. Sanger in
1953, the same year as the Watson - Crick model of
DNA was published. These two events signaled the
beginning of molecular biology. Insulin is synthe-
sized as a pre-proinsulin equipped with a signal
sequence that directs the molecules into the secreto-
ry vesicles. After the removal of this signal peptide,
proinsulin is formed that is stored in the cells. When
the glucose level in the blood increases insulin-
specific peptidases process the protein into the
functional final form. The A chain of bovine insulin
contains 21 amino acids and the B chain has 30, the
two chains are joined by disulfide bridges between
A7 and B7 as well as A20 and B19 residues and a
third disulfide bridge is formed within the A chain
between residues 6 and 11 protein structure. The A
chain is identical in humans, dogs, pigs and rabbits,
and the bovine B chain is identical to that of pigs,
goats, dogs and horses. The function of insulin
requires the presence of a receptor.
The insulin receptor protein is made of two and
two chains. The identical chains bind insulin
above the surface of the plasma membrane, whereas
the two chains reach inside the cell through the
membrane with their carboxy termini. Upon binding
of insulin, the chains become a specific protein
tyrosine kinase that first autophosphorylates and then
phosphorylates other proteins in a cascading series of
events. As a consequence a number of enzyme
activities are altered by the phosphorylation of
tyrosine and serine residues. These multiple reactions
explain why diabetes occurs in many forms and is
1006 Insulin
I
part of numerous other syndromes under the control
of a variety of genes and manifested in aneuploids
(Turners syndrome, Klinefelters syndrome and
Downs syndrome). Insulin receptor substrate-1 tends
to the integrin family of surface receptors and in this
way integrin and growth factor signaling are
connected (White MF 2003 Science 302:1710).
The various forms may be under the control of
autosomal dominant genes (diabetes insipidous ne-
phrogenic Type II, diabetes mellitus juvenile with
early onset). The latter was attributed, in one case, to a
substitution of serine for phenylalanine at the 24th
position of the chain. Only a single locus seems to
encode the human insulin structural gene in chromo-
some 11p15.5. The human INS and the mouse Ins
(chromosome 7) are expressed only from paternal
allele at some stages of development (imprinting). In
rats and mice two distinct loci are involved. Some
mutations interfere with the proteolytic processing of
proinsulin, resulting in its accumulation (hyperproin-
sulinemia) without any symptoms of diabetes.
Non-insulin-dependent diabetes was observed to
be associated with a mutation of the glucose
transporter-4 protein at residue 383 (Val [GTC]
Ile [ATC]) in some cases but not in others.
Vasopressin and oxytocin deficiency may also be
involved in diabetes. These two octapeptides regulate
muscle contraction and renal secretion. Diabetes is
generally associated with abnormalities of kidney
functions.
Autosomal recessive inheritance appears to account
for the juvenile-onset diabetes mellitus Type I and this
locus is assigned to human chromosome 6 in close
proximity to the HLA Class II genes. This locus is
probably a regulatory one, determining insulin
susceptibility with a penetrance of 71% for the
homozygotes and 6.5% for the heterozygotes. It was
reported that if at position 57 of the HLA DQ- chain
has Asp, then most probably diabetes was absent
whereas there was a high chance that this 57th residue
was non-Aspindiabetics. Other studies have indicated
that HLA genes DR3 and DR4 and HLA-DQ have
predisposing effects on the expression of diabetes.
Apparently HLA-DQw1.2 allele was protective but
HLA-DQw8 increased the chances of developing
insulin-dependent diabetes. Population genetic stud-
ies have also confirmed that having a non-polar amino
acid at position 57, the chances of developing diabetes
may increase by a factor of about 30.
X chromosomal linkage was observed for nephro-
genic diabetes insipidus Type I, and it was proposed
that this form of the disease was associated with a
defect in the vasopressin 2(V2) receptor.
Till recently, insulin for therapeutic purposes was
obtained exclusively from animal pancreas collected
at the slaughterhouses. By the use of recombinant
DNA human insulin can be industrially produced
with the aid of bacterial cultures and further
processing. The industrial production of human
insulin by genetic engineering is more successful
than that of other proteins because it does not require
glycosylation. In yeast, proinsulin mRNAis normally
produced but the translation of the message is very
inefficient. Human insulin has a definite advantage as
some patients may be allergic to the slightly different
animal protein. Lower than normal insulin resistance
is frequently associated with infections, diabetes,
obesity and some forms of cancer. In obese indivi-
duals, adipose tissues release increased amounts of
non-esterified fatty acids, glycerol, hormones, inflam-
matory cytokines and other factors that lead to insulin
resistance and Type 2 diabetes (Kahn SE et al 2006
Nature [Lond] 444:840). Obesity and diet-induced
insulin resistance may be reversed by salicylate or
disruption of IKKb (Yuan M et al 2001 Science
293:1673). Insulin resistance is mediated by tumor
necrosis factor and it decreases tyrosine kinase
activity in the insulin receptor by activating serine
phosphorylation (Kahn BB, Flier JS 2000 J Clin
Invest 106:473). White adipocytes transcribe a 750-
residue mRNA encoding the protein resistin (resis-
tance to insulin). Neutralization of resistin enhances
insulin-stimulated glucose uptake and active resistin
reduces the uptake. An increased level of ROS
can trigger insulin resistance (Houstis N et al 2006
Nature [Lond] 440:944). Insulin is degraded by an
evolutionarily well-conserved Zn
2+
-metalloprotease
(Shen Yet al 2006 Nature [Lond] 443:870). diabe-
tes, HLA, TNF, IKK, obesity, insulin-like
growth factor, insulin-receptor substrates, resis-
tin, S6 kinase, ROS, thiazolidinedione,
p110; Bell GI et al 1980 Nature [Lond] 284:26;
Steiner DF et al 1985 Annu Rev Genet 19:463;
Lizcano JM, Alessi DR 2002 Current Biol 12:R236;
historical: http://www.coreynahman.com/Information_
On_Insulin.html.
Insulin-Like Growth Factors (IGF-1, IGF-2): These are
required for the passage of the cell cycle from G1 to S
phase; they promote cell maintenance, metabolism
and cell division. A duplication of the Igf-1 gene
resulted in the development of mighty mouse,
animals with excessive muscle growth and some
potential health problems. The human genes for IGF-
1 and IGF-2 are located in chromosome 11p15-p11,
separated by about 1213 kbp. The human IGF-
2 gene is expressed only from the paternal chromo-
some. In mice, the IGF genes (chromosome 7) display
tissue-specific imprinting and are also expressed from
the paternal chromosome. Somatomedin, a mamma-
lian second messenger, has insulin-like functions in
regulating bone and muscle growth in conjunction
Insulin-Like Growth Factors 1007
I
with the pituitary hormone receptor. A minor 4.8-kb
mRNA generates the prepro-IGF2 whereas the major
6-kb mRNA encodes a post-transcriptionally regu-
lated IGF. The insulin-like growth factor receptor
(IGF-1R) and the insulin receptor belong to the
tyrosine kinase receptor family and regulate both
normal and malignant cell proliferation. The pater-
nally expressed IGF2 seems to controllike a QTL
muscle mass and fat deposition in pigs. Mice with
deletion of insulin and insulin-like growth factor have
normal pancreatic cell number yet develop diabetes
(Ueki K et al 2006 Nature Genet 38:583). signal
transduction, insulin, insulin receptor, imprint-
ing, growth factors, pituitary dwarfness, achon-
droplasia, somatomedin, mannose-6-phosphate
receptor, myostatin, pancreas, dog, Simp-
son-Golabi-Behmel syndrome, prostate cancer,
QTL; LeRoith D et al 1992 Ann Intern Med
116:854; Jiang F et al 2001 Dev Biol 232:414;
structure of insulin-like growth factor receptor: Ward
CWet al 2001 Mol Pathol 54:125.
Insulinoma: A relatively benign pancreatic cancer
leading to excessive secretion of insulin.
Insulin-Receptor Protein (IR): This heterotetrameric
membrane protein is a tyrosine kinase (related to the
epidermal growth factor [EGFR] family); its defi-
ciency leads to Donohue syndrome. The enzyme
protein tyrosine phosphatase (PTP-1B) dephosphor-
ylates IR and as a consequence in diabetes type II
disease, although the cells can make insulin, they are
unable to respond to this hormone because of the
expression of PTP-1B. The Rabson-Mendenhall
disease (INSR, 19p13.2) is due to deficiency of IR.
insulin, diabetes, obesity, Donohue syn-
drome, Rabson-Mendenhall disease, insulin-like
growth factor, GLUTs; structure: McKern NM et al
2006 Nature [Lond] 443:218.
Insulin-Receptor Substrates (IRS1, IRS2, IRS3, IRS4):
After multiple site tyrosine phosphorylation they bind
to and activate phosphatidylinositol-3-OH kinase
and other proteins with SH2 domains. Defects in
IRS2 may be responsible for insulin-independent
diabetes. IRS1 and IRS2 are essential for normal
embryonic and post-natal growth. The IRS
/
in-
dividuals by 30 days reach less than 1/4 of the wild
type weight and the reproductive capability
especially of females is impaired. insulin,
insulin-like growth factor, SH2, diabetes
Insulitis: This is an autoimmune inflammation caused
by infiltration of the islets of Langerhans by T
lymphocytes. autoimmune disease, Langerhans
islets, T cell, lymphocytes, diabetes mellitus
INT Oncogene: INT1 is assigned to human chromosome
12q13 and to mouse chromosome 15. The product of
Drosophila gene wingless (wg) is a homolog and
therefore the gene is sometimes referred to as WNT.
INT4 (human chromosome 17q21-q22, mouse chro-
mosome 11) is also homologous to the Drosophila wg
gene. In mammary carcinomas INT1 is frequently the
target site for insertion and inactivation. INT2 is a
mammary tumor gene assigned to human chromo-
some 11q13 and its only relation to INT1 is its
presence in mammary tumors. INT2 product shows
some relationship to fibroblast growth factor 6. INT3,
another mammary tumor gene, encodes a transmem-
brane protein. oncogenes, FGF, transmembrane
proteins, morphogenesis in Drosophila, WNT1
Intasome: Abacterial nucleoprotein complex, including
a negative supercoiled phage DNA, wrapped around
by several copies of the phage-encoded integrase and
the bacterial integration host factor protein (IHF).
DNA bending by Xis regulatory proteins promotes
the. formation of the excisive intasome, but antag-
onizes the formation of an integrative intasome. Xis
stabilizes the synaptic complex by directly interacting
with Int bound to the arms of the phage. Xis
recognizes a single binding site. Three Xis monomers
work in concert to substantially bend the DNA by
forming a micronucleoprotein filament (Abbani MA
et al 2007 Proc Natl Acad Sci USA 104:2109).
integrase, IHF; Chen H et al 1999 J Biol Chem
274:17358; Esposito D et al 2001 Nucleic Acids Res
29:3955.
Integr8: genome and proteome browser: http://www.
ebi.ac.uk/.
Integral Membrane Protein: Refers to a protein in the
membrane without covalent linkage to it and it is
bound there by about two dozen uncharged and/or
hydrophobic amino acids. The majority of the
integral transmembrane proteins contain tightly
packed -helices and they are called helix-bundle
class. These membrane proteins insert co-translation-
ally and fold in the endoplasmic reticulum. In
eukaryotes insertion is mediated mainly by the
Sec61 translocon. translocon, transmembrane
proteins
Integrase: A protein that specifically recognizes
transposon or phage (att) or yeast integration sites
and opens them up for insertion to take place. The
integrase makes a staggered cut in the DNA and the
enzyme is covalently bound to the DNAvia a catalytic
tyrosine (Tyr
342
). A Holliday intermediate is formed
and after a second exchange (and removal of the
40-kDa protein) the recombination product is gener-
ated. There is tremendous structural variation among
more than 60 integrases yet a four-residue catalytic
1008 Insulinoma
I
unit is highly conserved. The position of the integrase
(IN) in the Ty/gypsy group of transposons is 5-
LTR-gag-protease-reverse transcriptase-RNaseH-IN-
LTR-3 and among the Ty1/copia-like elements
5-LTR-IN-reverse transcriptase-RNaseH-LTR-3. The
same enzyme may catalyze both integration and
excision as determined by the recombination direc-
tionality factors (RDF). Integrases can be used for the
insertion of genes in specific locations as a means
to gene therapy. integration, Cre, Flp, aspar-
tate protease, att sites, transposable elements,
lambda phage [site 27815], INI1, IHF, inta-
some, Holliday structure, Holliday model,
integron, Ty, copia, retroviruses, RAG1,
disintegration, FRET; Hindmarsh P, Leis J 1999
Microbiol Mol Biol Rev 63:836; Craigie R 2001 J
Biol Chem 276:23213; Lewis JA, Hatfull GF 2001
Nucleic Acids Res 29:2205; Campbell A et al 2002
Gene 300:13; Radman-Livaja M et al 2005 Proc Natl
Acad Sci USA 102:3913; structure and allosteric
control: Biswas Tet al 2005 Nature [Lond] 435:1059.
Integrated Circuit (chip): This is an electronic circuit
within a single piece of semiconducting material.
semiconductors
Integrated Map: This is based on the combined
information on genetic linkage and physical
mapping. mapping genetic, physical map, skel-
etal map, unified genetic map
Integrating Vector: yeast integrating vector
Integration: ADNAsequence is inserted at both termini
by covalent linkage into the host DNA. The DNA
structure (bends) affects the site of integration. HIV
integrates non-randomly either into purified naked
DNA or preferentially into CpG stretches modified
by cytosine methylation and within distorted nucleo-
somal DNA. The murine leukemia virus (MLV)
integrates non-randomly, preferably into the major
groove of the nucleosomal DNA. Retroviruses most
commonly select DNase hypersensitive sites and
stretches involved in active transcription. Agrobac-
terial vectors are usually integrated into the non-
translated regions of potentially expressed genes and
similar predilections have been observed in the
bacterial transposons. The different yeast Ty elements
also exhibit preferences. The transfer of foreign DNA
into mammalian genomes either by infection or
transformation may result in genome-wide methyla-
tion at sites remote from that of the integration and
may alter the pattern of expression of genes in the
recipient genomes. The integration of the DNA into
the human genome may be mediated by protein
Metnase, which methylates histone H3 lysine 4 and
lysine 36, required for opening the chromatin.
Metnase increases non-homologous end-joining
repair of double-strand breaks. This protein has a
SET domain as well as transposase and nuclease
domains required for the uptake of exogenous DNA
into chromosomes (Lee S-H et al 2005 Proc Natl
Acad Sci USA 102:18075). Ty, T-DNA, DNase
hypersensitive sites, MLV, HIV, transposons,
RIP, MIP, methylation of DNA, transforma-
tion, SET motif, histones, non-homologous
end-joining; Mller K et al 2001 J Biol Chem
276:14271.
Integration: In mathematics, this is the finding of a
function of which the integrand is a derivative or
finding an equation among finite variables that is
the equivalent of the differential equation integrated.
F(x) =
_
f(x)dx and
dFx
dx
f(x). derivative
Integration Host Factor: IHF
Integration Plasmid: This has homologous sequences to
the chromosome and after transformation, by recom-
bination, it may be inserted in multiple copies into the
yeast chromosome. Linearization of the plasmid may
increase its efficiency of integration 101000 fold.
Integrative Circuits in Signal Transduction: Multiple
kinases initiate a common response. signal trans-
duction
Integrative Physiology: This monitors the total function
of organs in a non-invasive manner.
Integrative Suppression: Refers to the elimination of the
manifestation of a genetic defect by insertion of a
normal copy of the gene. (See Brasch MA, Meyer RJ
1988 Mol Gen Genet 215:139).
Integrator: This is a 12 subunit attachment to RNA
polymerase II. Two of the subunits are similar to the
RNA transcript cleavage and polyadenylation factor
complex. The integrator is recruited to the U1 and U2
small nuclear RNA genes and mediates the proces-
sing of the 3 end of snRNA and interacts with the C
terminal domain of the polymerase. (See Baillat D
et al 2005 Cell 123:265).
Integrator Gene: A hypothetical regulator and coordi-
nator of eukaryotic genes. (See Wadgaonkar R et al
1999 J Biol Chem 274:1879).
Integrins (ITG): These are a part of the heterodimeric
family of integral membrane proteins that stretch out
to the intercellular space and form the extracellular
matrix. In connection with fibronectin, other ligands
and ICAM integrins control cell adhesion and cell
shape, the development of Drosophila halteres, legs
and wings, signaling, intracellular Ca
2+
, inositol and
lipid metabolism (see Fig. I40). Leukocytes contain a
variety of integrins that are involved in inflammatory
and immune responses. Integrins have and
Integrins 1009
I
subunits that are translated separately and their
association is not by covalent linkage. Some of the
integrin and subunit genes have been assigned to
human chromosome 2, whereas -7 integrin appears to
be in chromosome 12. The -6 integrin forms 991-
residue extracellular, 23-amino transmembrane and a
36-amino acid intracellular domain. Integrin is asso-
ciated in the cells with a 59K-serine/threonine protein
kinase, containing four ankyrin-like repeats. This
integrin-linked kinase (ILK) possibly regulates integ-
rin-mediated signal transduction. Integrins, by binding
to ligands, may control substratum adhesiveness and
therefore cell migration (see Fig. I41). Integrins
integrate the extracellular signal systems with the
cytoskeleton. Focal adhesioncomplexes, containing1
integrin, talin, actin and vinculin, are formed upon
activation by the extracellular matrix.
The integrin-mediatedsignal transduction pathwayis
shown in the Fig. I41. This complex is attached to the
cytoskeleton and localized signal transducting mole-
cules. Pre-existing mRNAs are targeted to cytoskeletal
micro-compartments where integrin controls their
translation in the vicinity of the signal receptor sites.
Integrins appear to be involved in fertilization by
binding fertilin molecules. They are involved in the
control of the cell cycle and apoptosis. In the absence of
integrins 3 or 3/5 or selectins mice are susceptible
to enhanced tumor growth (Taverna D et al 2004 Proc
Natl Acad Sci USA 101:763). They signal to the RAS
and the ERK systems. fibronectin, cadherin,
talin, CAM, SOS, ICAM, FAK, Src,
Grb2, RAS, MAPK, ERKI, GAP, cPLA
2
,
ankyrin, signal transduction, angiogenesis, epi-
dermolysis, lipoxygenase, atresia, cell migration,
CD98, calreticulin, talin, actin, vinculin,
caveolin, myopathy, metastasis, fertilin,
T cell receptor, invasin; Clegg DO 2000 Mol Cell
Biol Res Comm3:1; Calderwood DA et al 2000 J Biol
Chem 275:22607; Hynes RO 2002 Cell 110:673;
structure: Xiao T et al 2004 Nature [Lond] 432:59;
http://www.geocities.com/CapeCanaveral/9629.
Integron: This is a mobile DNA element, a transposon
with a cassette, flanked by a 5 and a 3 conserved
sequence. The internal cassette can accommodate
antibiotic resistance genes by site-specific recombi-
nase (integrase, intI) located in the 5 element and a
closely linked attI (attachment) site. It contains
several rightward (P2, P2, P4 and P5) and one
leftward (P3) promoter sites and a ribosome-binding
site. The 3 element includes a conserved sulfonamide
resistance gene. Sulfonamide resistance stems from a
lack of sensitivity of dihydropteroate synthase to
sulfonamide inhibition. Its origin, however, is unclear
since sulfonamides are synthetic antibiotics. Dihy-
dropteroate is a precursor of folic acid. The integron is
the vehicle of antibiotic resistance genes among
various types of bacteria. Integrases bear 4358%
homology to similar sequences of bacteriophages.
Super-integrons carry several cassettes and can
accommodate multiple antibiotic resistance genes
and therefore make fighting disease very difficult.
Integrons are an important means of generating
genomic diversity in prokaryotes. Determining the
crystal structure of integrons has revealed that DNA
target site recognition and synaptic assembly do not
depend on the canonical DNA sequence rather two
flipped-out bases interact in cis and trans with the
integrase (MacDonald D et al 2006 Nature [Lond]
440:1157). gene cassette, integrase, folic acid,
transposon, R plasmid, shoufflons, pathoge-
nicity island; Rowe-Magnus DA et al 2001 Proc Natl
Acad Sci USA 98:652; Gillings MR et al 2005 Proc
Natl Acad Sci USA 102:4419.
Integrin
Src Grb 2
Fak SOS
RAS
GTP
GAP
MAPK Arachid. A Lipoxygenase
P P
gene expression
cPLA2
P
cytoskeleton
cell adhesion
Figure I40. The integrin-mediated signal transduction pathway. (For symbols see individual entries, Arachid. A =
archidonic acid) After Clark EA and Burggie JS 1995 Science 268:233
E
x
t
r
a
c
e
l
l
u
l
a
r

m
a
t
r
i
x
C
e
ll
m
e
m
b
r
a
n
e
C
y
t
o
s
k
e
le
t
o
n
chain

Divalent
cations
Figure I41. Integrin on the cell surface
1010 Integron
I
Integument: Refers to the maternal somatic tissue layers
that surround the ovule of plants and give rise to the
seed coat. Thus, the integument may show delayed
inheritance. megagametophyte development, de-
layed inheritance
Inteins: These are elements that are inserted into
proteins before the completion of its sequence and
removed thereafter; they are protein-splicing ele-
ments. They are spliced out post-translationally by
autocatalytic proteolysis and ligation. The intein
system can be used for genetic engineering. Part of
a herbicide resistance gene-intein fusion was trans-
formed into the nucleus and the other part of the same
gene, equipped with a carboxy-terminal intein, was
introduced into the chloroplast genome. The nucle-
arly encoded herbicide protein-intein fragment mi-
grates to the chloroplasts and reconstitutes the full
length herbicide resistance. Since the chloroplast
located fragment is not transmitted by out-pollination
to plants in the environment there is no effective
spread of herbicide resistance (Chin HG et al 2003
Proc Natl Acad Sci USA 100:4510). Some inteins are
site-specific endonucleases. They may also function
as transposons and insert their coding sequences into
intein-less genes. Inteins have different structures
and are found in prokaryotes, algal chloroplasts and
other lower eukaryotes. Inteins may provide evi-
dence of horizontal transmission of nucleotide
tracts during evolution. intron, transmission,
extein, herbicides, semi-synthesis, protein
engineering, homing endonucleases; Paulus H
2000 Annu Rev Biochem69:447; Liu X-Q2000 Annu
Rev Genet 34:61; Gogarten JP et al 2002 Annu Rev
Microbiol 56:263; Perler FB et al 1994 Nucleic Acids
Res 22:1125; Evans TCet al 2005AnnuRevPlant Biol
56:375; http://www.neb.com/neb/inteins.html.
Intellectual Property: copyright, patent
Intelligence Quotient (IQ): human intelligence
Intelligent Design: This theory of organic evolution does
not accept either Darwinism or creationism in its
entirety and postulates that the evolution/development
of the complexity of biochemical structures requires an
intelligent design. Genetics can deal only with experi-
mental facts that can be tested with scientific procedures
without subjective assumptions or faith. evolution,
Darwinism, creationism, scopes trial
Intensifier: Refers to an animal or plant gene that
intensifies (darkens) color.
Interaction, Molecular: Such interaction generally
requires physical contacts between/among the com-
ponents such as hydrogen bonding and van der Waals
forces. There is another type of interaction, interac-
tion without direct contact, governed by linkage
thermodynamics. Macromolecules and biopolymers
share a common milieu within the cell conformations.
The equilibria are also modulated by the solute
solvent interactions. The response of hemoglobin to
CO
2
changes the blood pHis one example of through-
solution communication. It demonstrates a response
in one type of tissue to a metabolic state in another
through the shared solution. Such mechanisms seem
to play a significant role in cellular regulation.
ligands, hydrogen bond, van der Waals forces;
Vlker J, Breslauer KJ 2005 Annu Rev Biophys
Biomol Struct 34:21.
Interaction Trap: This procedure is basically similar
to the two-hybrid method where the interaction of
two or more molecules permits a biological or phys-
ical observation. two-hybrid method; Toby GG,
Golemis EA 2001 Methods 24:201.
Interaction Variance: This is due to epistasis between
quantitative traits and the effect of the environment on
gene expression. analysis of variance, epistasis
Interactome: Refers to the system in the proteome
where proteins interact and cooperatively determine
function(s). Using binary proteinprotein interac-
tions, mainly yeast, two-hybrid system large-scale
interactions can be developed. These interactions of
thousand of genes can shed light on interacting
proteins in the human genome, including genes
responsible for disease. proteome, protein inter-
actions, gene product interaction, protein com-
plexes, genetic networks, gateway cloning,
protein-nucleic acid interactions, ORFeome,
E-map; Ito T et al 2001 Proc Natl Acad Sci USA
98:4569; Ge H et al 2001 Nature Genet 29:482;
Rual J-F et al 2005 Nature [Lond] 437:1173, atlas of
yeast interactome: Collins SR et al 2007 Mol Cell
Proteomics 6:439; http://dip.doe-mbi.ucla.edu/; pro-
tein, nucleic acids interactions: http://biozon.org/;
human interactome: http://www.mdc-berlin.de/unihi.
Interactor: In the evolutionary context, this is an
individual(s) who interacts with the biotic and abiotic
environment and through the interaction his trait(s)
imparts reproductive success and the hereditary
material is transmitted to the progeny.
Interalign: This is a multiple sequence alignment
program for proteins. CLUSTAL W, MAFFT-5;
Pible O et al 2005 Bioinformatics 21:3166.
Interallelic Complementation: allelic complementation
Interband Region: In polytenic chromosomes the
relatively lighter stained space between the charac-
teristic darkly stained bands is known as the interband
region (see Fig. I42).
Interband Region 1011
I
Figure I42. Band and interband regions
Interbreeding: Refers to a process where individuals of
different genotypes in a population may mate.
random mating, mating systems
Intercalating Mutagens (such as acridines and some
nitrogen mustards): These can insert within nucleo-
tide sequences and cause frameshift mutations, short
insertions and deletions. Intercalation also leads to the
separation of the base pairs, lengthening and
untwisting of the double helix. acridine dye,
nitrogen mustards, frameshift mutation
Intercellular: Denotes located between cells. intra-
cellular
Intercellular Immunization: The antibody production is
ectopic and their secretion depends on cells other than
lymphocytes. The expression of the immunoglobulin
genes can be directed to specific cells by employing
cell type specific promoters and enhancers in
transformation. Such manipulations may block the
expression of genes by the antibodies and may reveal
the consequences for their function, for development
or disorder and possibly for therapy targeted with
high specificity. Besides the transgenic approach,
grafting specific cells on to an appropriate tissue may
be employed. ectopic, lymphocytes, immuni-
zation, neuroantibody, ablation, genetic engi-
neering, intracellular immunization
Intercept: correlation [in a linear regression a = Y- bx].
Interchange: This refers to the reciprocal translocation
of chromosomes. translocations
Interchange Trisomic: trisomic tertiary, trisomic
analysis
Interchromosomal Interactions: Interferon gamma
(IFN-, 12q14) defines the development T
h
1 helper
cells and interleukin-4 (IL4, 5q31) defines the
development of T
h
2 helper cells, which play different
roles in the immune system. The locus control region
of the T
h
2 gene coordinately regulates the cytokine
genes Il4, Il5 and Il13 although these sites are spread
over 120 kb region within the same chromosome
(intrachromosomal interaction). These elements are
closely juxtaposed in the conformational state of the
chromatin. In the nucleus each chromosome has its
own particular territory, in the mouse the IFN- gene
in chromosome 10 and the regulatory cytokine
region of the T
h
2 gene in chromosome 11 also
interact despite being in different chromosomes. Such
interchromosomal interactions may have general
significance for the development of disease.
interferon, interleukin, looping of DNA;
Spilianakis CG et al 2005 Nature [Lond] 435:637.
Interchromosome Domain Compartment: The space
between chromosome territories may be the area of
transcription and RNA processing. chromosome
territory
Intercistronic Region: Refers to the number of nucleo-
tides between the end of one gene and the beginning
of the next one. cistron
Intercross: Refers to mating between individuals
(siblings) of the same parentage.
Interest: This is the rate to be paid for the use of funds.
Interest = (total amount of funds x interest rate x
years)/100. Compound interest is the total amount of
interest due on both the principal investment and the
accumulated interest over time. For example: at 5%
interest in 20 years $100 investment will increase in
value to (1.05)
20
100 = $265.33. The interest rate is
normally compounded monthly or quarterly and more
elaborate formulae are used for precise calculations.
In case money is borrowed it is necessary to know
the cost. For this purpose a very simple constant ratio
formula is: i =
2mI
Pn1
where m = number of payment
periods within one year, I = the discharge rate, P =
principal amount, n = the total number of payment
periods. If $100 is borrowed and is supposed to be
repaid in 12 equal monthly payments at a charge of
6% discount, the effective interest rate is: i =
2x12x6
94121

144
1222
0:1178 , i.e., 11.8%. Financial institutions
use a more accurate formula leading to a slightly
different outcome.
Interfacial Enzymology: The enzymes act on substrates
located on a surface and hence their activity is
regulated by the concentration of the substrate on the
surface. Such enzymes may be found within or on
cellular membranes.
Interference, Bacterial: One strain excludes the others
from infection or colonization sites. The interference
is usually mediated by the inhibition of the synthesis
of virulence factors or surface receptors. RNA
interference
Interference, Chromatid: chromatid interference
Interference, Chromosome: One crossing over may
either reduce (positive interference) or increase
(negative interference) the occurrence of additional
ones. The availability of complete nucleotide
sequences of the chromosomes permits a detailed
analysis of the molecular basis of the phenomenon.
Interference may proceed along one or two pathways
according to the organisms. In yeast, the MSH4
mutations (involved in mismatch repair) eliminate
interference although they reduce crossing over by
1012 Interbreeding
I
only 5070%. The MSH4 homolog HIM-14 in
Caenorhabditis completely prevents crossing over.
In the case of humans, there is statistical evidence for
the two-pathway model which has implications for
the precision of genotyping (Housworth EA, Stahl
FW 2003 Am J Hum Genet 73:188). coincidence,
coefficient of coincidence, mapping function,
chromatid interference, mismatch repair; Zhao H
et al 1995 Genetics 139:1045; Browman KW, Weber
JL. 2000 Am J Hum Genet 66:1911; Tapper WJ et al
2002 Ann Hum Genet 66:75.
Interference, Dominant: The interference changes a
transcriptional activator into a repressor. activator
protein, repressor
Interference, Negative: coincidence
Interference RNA: RNAi, RNA interference
Interferon: Refers to specific cellular glycoproteins that
develop after a viral infection or as a reaction to RNA
or other compounds, and they show antiviral activity
and possibly anti-tumor activity. Double-stranded
RNA (dsRNA) and siRNA can activate interferon
genes in mammals through the dsRNA-dependent
protein kinase (PKR) and through the Jak-STAT
signal transduction route (Sledz CA, Williams BR
2004 Biochem Soc Trans 32:952). When associated
with all-trans retinoic acid IFN is particularly
effective in inhibition, including cancer cell growth
inhibition. Interferons have three major forms, IFN-,
and . Interferons can be produced following
transformation in a variety of cells (yeast, silkworm,
mouse, hamster, etc.). Interferons produced by
leukocytes contain predominantly the type. Lym-
phoblastoid cells (lymphocytes stimulated by an
antigen) have 90% and 10% interferons. Induced
fibroblasts mostly contain the chain. The
interferon is produced by antigen- or mitogen-
stimulated T lymphocytes. Interferon-induced pro-
tein genes have been traced to human chromosomes
21, 10, 4, and 1. Intereferons may interfere with
protein synthesis by causing phosphorylation of
eukaryotic peptide chain initiation factor eIF-2.
Interferon (leukocytic interferon, IFNA1) genes
(up to 30) have been located in human chromo-some
9p21-p13. One of these genes, activated by the
double-stranded viral replication intermediate, is 2-
5-oligoadenylate synthetase, which in turn activates
the latent ribonuclease L. RNase L degrades single-
stranded RNA, the viral genome. Another induced
enzyme is the dsRNA-activated protein kinase R
(PKR). PKRmay mediate apoptosis and may assist in
establishing persistent infections by several viruses.
An interferon receptor (antiviral protein, AVP) has
been assigned to human chromosome 21q22. Trans-
locations of the INFA have been identified in
leukemia patients. It has been claimed that intranasal
use of interferon may prevent common cold.
Natural IFN-producing cells (dendritic cell precur-
sors) that express CD4 and major histocompatibility
class II synthesize IFNA.
Interferon -1 (fibroblast interferon/IFB1, human
chromosome 9p21-pter) is structurally homologous
to interferon. In patients suffering from acute
monocytic leukemia, translocations of IFB1 to
chromosome 21 were observed and the break point
was within this gene at about 17-cM from the site of
the ETS-2 oncogene (chromosome 21q22.1-q22.3).
Chromosome 9 contains several interferon genes.
Interferon -2 (IFNB2 (human chromosome 7p21-
p15) is induced by the tumor necrosis factor (TNF)
and interleukin (IL-1) when interferon -1 (IFNB1) is
not induced. It is identical to the B-cell differentiation
factor (BSF2) and hybridoma growth factor. Interfer-
on -3 (IFNB3) is in human chromosome 8.
Interferon (IFNG, human chromosome 12q14)
induces the expression of HLA class II genes. The
induction is modulated by a factor in human
chromosome 16 (probably a receptor) and by another
factor in chromosome 21 that may control the
transduction of the interferon signal. In RAG
(recombination activating) cells a human chromo-
some 6 factor is also required in human-rodent cell
hybrids. IFNG induces the production of a 98-residue
polypeptide (IP-10, chromosome 4q21) and other
activating polypetides. Hereditary interferon recep-
tor deficiency increases the susceptibility to myco-
bacteria and Salmonella infections. The interferon
regulatory factor (IRF) family includes the interferon
consensus sequence binding protein (ICSBP, ex-
pressed constitutively in B lymphocytes) and other
transcription factors (IRFs). Their N-terminal region
binds to the DNA (IFN-stimulated responsive
element, ISRE) and the C-terminal contains the
regulatory sequences. lymphokines, leukemia,
interferon response element, Bcell, hybridoma,
modulation, signal transduction, receptor
protein, IRF, interleukin, CD4, MHC, den-
drocyte, mycobacterium, allergy, PKR, Jak-
STAT, granulocyte, killer cell, RNAi; Stark GR
et al 1998 Annu Rev Biochem 67:227; Taniguchi T,
Takaoka A 2001 Nature Rev Mol Cell Biol 2:378;
Sen GC 2001 Annu Rev Microbiol 55:255; inter-
ferons in virus-host relationship: Garcia-Sastre A,
Biron CA 2006 Science 312:879.
Interferon Receptors: IFN and share the same 63.5-
kDa receptor. The IFN, IFN and IFN receptors are
located in the same cluster (21q-q22.1). The IFN
receptor binds the ligand at the 245-amino acid ex-
tracellular domain whereas the 222-amino acid
intracellular domain is involved in signal transduc-
tion. interferon, interferon regulatory factors,
signal transduction Jak-STAT
Interferon Receptors 1013
I
Interferon Regulatory Factors (IFR): These bind to the
upstream regions of both and interferon genes and
serve as a transcription activator (IRF-1) or (IRF-2)
have an antagonistic effect. There are several
additional IRFs. IRF1 binds to two regulatory
elements (PRDI and II) in the IFN genes promoter.
These elements respond to Jun and NK-B, which
bind to the nearby PRDII and IV. They compete for
the same cis element. Both factors have been assigned
to human chromosome 5q23-q31. The IFR-2 protein
is identical to HiNF. The IRF-E DNA-binding site has
the consensus G(A)AAA(G/C)(T/C)GAAA(G/C)(T/
C). Some IFRs (IURF-4, vIRF) are elevated in certain
cancers. interferon, upstream, cis-acting ele-
ment, leukemia, macrophage, cytokines,
transcription factors, CCE, histones, HiNF,
Jun, NK-B; Taniguchi T et al 2001 Annu Rev
Immunol 19:623.
Interferon Sequence Response Element (ISRE):
AGTTTCNNTTTCN[C/T]. GAS, signal trans-
duction Jak-STAT, interferon, interferon receptors
Interferon-Induced Proteins: Located in different hu-
man chromosomes 1, 2, 4, 10, 12, 21. Interferon-
inducible cytokine IP-10 (human chromosome 4q21)
is located close to the break point associated with
monocytic leukemia. (Monocytes are phagocytic
mononuclear leukocytes that develop into macro-
phages in the lung and the liver). IP-10 has substantial
homology to several activating peptides and it may
control inflammatory responses. cytokines, leu-
kemia, macrophage
Intergenic Complementation: This provides evidence
that the two genes are not allelic but belong to
separate loci. allelic complementation, allelism
test
Intergenic Regions: These regions represent the bulk of
the DNA, which contains in higher eukaryotes only a
small percentage of coding sequences. Recent
estimates have revealed that in Drosophila 15.6%
of intergenic transcribed regions function as missed
or alternative transcription start sites used by 11.4%
of the expressed protein-coding genes. At least 85%
of the fly genome is transcribed and processed into
mature transcripts (Manak JRet al 2006 Nature Genet
38:1151). The distinction between genic and inter-
genic regions is becoming blurred because of over-
lapping transcripts and human genes frequently
coalesce into larger genomic domains.
In yeast the histone deacetylase Rpd3, which exists
in two forms, RpdC(S) and RpdC(L), are recruited to
promoters to repress transcription. Chromatin immu-
noprecipitation indicates that the Eaf3 subunit of
RpdC(S) is recruited to Histone3 lysine 36, which is
methylated by a SET domain of RNA polymerase II
resulting in deacetylation. This process subsequently
erases transcription elongation-associated acetylation
and suppresses intragenic transcription initiation
(Carrozza MJ et al 2005 Cell 123:581; Keogh M-C
et al 2005 Cell 123:593).
The transcripts of non-coding intergenic sequences
seem to play regulatory roles (Schmitt S et al 2005
Genes Dev 19:697). Alternative promoters specify
some of the intergenic transcripts to tissues. Nearly
half of the differences between humans and chimpan-
zees are due to intergenic transcription (Khaitovich P
et al 2006 PLoS Genet 2(10):e171). A large fraction
includes mobile elements with evolutionary signifi-
cance. introns, SET domain, histone acetyl-
transferases, transposable elements, selfish DNA,
ENCODE; Kondrashov AS, Shabalina SA 2002
Hum Mol Genet 11:669; Cliften P et al 2003 Science
3001:71.
Intergenic Spacers (IGS): Sequences between rRNA
genes, which have very short transcripts (appear like
feathers) but may contribute to initiation of transcrip-
tion (see Fig. I43). ITS, tRNA, pol III
Gene
Gene
Gene
Spacer Spacer
Figure I43. Intergenic spacers. Image courtesy of
Spring et al 1976 J Microsc Biol 25:107
Intergenic Suppressor: One mutation suppresses the
expression of another situated in a different locus.
The suppressor normally encodes a mutant tRNA.
suppression
Intergenic Transcript: This contains sequences from
two separate genes. The mRNA of a large protein
transcribed from 20 exons of chromosome 14
contains the intercalated 188 nucleotides exactly
matching a part of chromosome 1. The chromosome 1
sequence has no reading frame and does not code for
a protein from its transcript (except from the 188 base
within chromosome 14 mRNA). gene fusion;
Claverie JM 2005 Science 309:1529.
Interkinesis: interphase
Interleukins: Proteins secreted by white blood cells,
phagocytes, B lymphocytes and are involved in
stimulating growth and differentiation of lympho-
cytes concerned with the natural defense system of
the body. lymphokines, IL-1, IL-2, IL-3,
IL-4, IL-16, etc.; http://www.gene.ucl.ac.uk/
nomenclatrure/genefamily/interleukins.html.
Interlocking Bivalents: When another chromosome
passes through the terminalizing chiasmata (ring
1014 Interferon Regulatory Factors
I
bivalents), the non-homologous chromosomes may
be trapped (interlocked) within the ring (see Fig. I44).
ring bivalent Rasmussen; SW 1976 Chromosoma
54:245.
Centromere Centromere
Figure I44. Interlocking bivalent
Interlogs: Refers to the potential interactions of protein
based interactome models. interactome, protein
interactions
Intermediary Metabolism: In this process, enzymes
within the cells produce energy from nutrients and
use it to synthesize other compounds or organize
cellular components.
",5,0,1,0,105pt,105pt,0,0>Intermediate Filaments:
These are ubiquitous 10 nm protein filaments
abundant in eukaryotic cells and are encoded by at
least 50 genes. They are composed of keratin, desmin,
vimentin, neurofilament proteins, glial fibrillary
acidic protein (GFAP), lamin, etc. Their anomalies
may result in epidermolysis, keratosis and possibly
other skin diseases. filament, keratin, keratosis,
epidermolysis, desmosome, vimentin, la-
mins, skin diseases; Kreplak LK, Fudge D 2007
Bioassays 29:26; human intermediate filament data-
base: http://www.interfil.org/.
Intermedin: A melanocyte stimulating protein factor.
melanocyte
Internal Control Regions (ICR): A box
Internal Image Antibody: An anti-idiotypic antibody
which binds to the antigen binding site of the
complementarity determining region of an antibody
rather than to the antigen. anti-idiotypic antibody,
immunoglobulin, antibody, complementarity-
determining region, antigen
Internal Membrane: Refers to membranes within the
cell excluding the plasma membrane.
Internal Promoter: promoter
Internal Transcribed Spacers: ITS, ETS, tRNA
Internalins: These are proteins mediating the bacterial
uptake by eukaryotic cells. The internalization
requires co-factors such as cadherin, catenin, actin,
PI-3 kinase and the reorganization of the cytoskele-
ton. cytoskeleton, phosphoinositides, cadherin,
catenin, actin; Schubert WDet al 2001 J Mol Biol
312:7387.
Internally Eliminated Sequences (IES): During the
formation of the macronuclei of Ciliates chromosome
diminution and fragmentation occurs. The DNA
deleted involves repetitive sequences but the IES
are not a part of the repetitive sequences, and may
even include functional genes. There is a variation in
the location and sequences of the IES in different
related species. chromosome diminution, Para-
mecia, Ascaris, macronucleus; Garnier O et al
2004 Mol Cell Biol 24:7370; Huvos PE 2007 J
Eukaryot Microbiol 54:73.
International Prognostic Index (IPI): Marks an attempt
by the European Society for Medical Oncology
to predict the risk/survival of some cancers under
standard conditions of treatment. (See Lopez-
Guillermo A et al 1994 J Clin Oncol 12:1343).
International Protein Index (IPI): This is an integrated
database for proteomics. proteomics; Kersey PJ et al
2004 Proteomics 4:1985; http://www.ebi.ac.uk/IPI.
Internet: Refers to a complex system of interconnected
electronic communication networks.
Internet2: This is a consortium of more than 200 uni-
versities in partnership with industry and government
for advanced telecommunications. ABILENE,
BIRN; http://www.internet2.edu/.
Internode: Refers to a segment of a plant stem between
nodes (leaves) (see Fig. I45).
Internode
Figure I45. Internode
Interologs: These are conserved protein-protein inter-
actions facilitating the identification of protein net-
works. genetic networks; Matthews RL et al 2001
Genomes Res 11:2120.
Interoperability: Refers to different computer programs
through which computers can communicate with
each other.
Iterons: Denotes the initiator binding sites of the
replication origin. iDNA
Interorganismal Genetics: Flors model
Interphase: This refers to the phase of the cell cycle when
mitosis is not in progress. During the interphase
between mitoses the cells are actively synthesizing
DNA (S phase) and during the G phases other
molecules are produced and the cellular organelles
are dividing (see Fig. I46). In meiotic divisions the
DNA synthesis is limited to repair and all DNA is
Interphase 1015
I
produced during the interphase preceding meiosis.
According to the traditional view, during interphase the
chromosomes are more relaxed and stretched. A high-
resolution multicolor FISH banding analysis of human
chromosome 5 indicates that in both lymphocytic and
HeLa cells the length of interphase chromosomes is
about the same as in the metaphase although they
display bending and folding (Lemke J et al 2002 Am J
Hum Genet 71:1051). Recent data attribute the
increasedlengthobservedbyclassical microtechniques
to an artifact caused by the fixatives and staining. cell
cycle, mitosis, meiosis, FISH
G1-S-G2-M G1-S-G2-M
Figure I46. Interphase
Interpolation, Linear: See the procedure described
under F
2
linkage estimation
Interpro: This is a database of protein families, domains
and functional sites in which identifiable features
found in known proteins can be applied to unknown
protein sequences. http://www.ebi.ac.uk/interpro/.
Interracial Human Hybrids: The genetic distance based
on gene frequencies is relatively short evolutionary
distance. among the various human races and despite
the theoretical expectation of the deleterious effects
of breaking up co-adapted genetic sequences, inter-
racial hybrids suffer no physical harm. Problems may
arise, however, in cultural adaptation because the
hybrids are normally classified socially with the
minority race (whatever the majority is) and discrim-
ination against minorities is not uncommon in all
racial, ethnic and cultural groups. Despite the great
similarities of the genetic structure of all primates,
no hybrids between humans and other primates
have been verified. Somatic cells of all types of
eukaryotesincluding those of humanscan, how-
ever, be hybridized but cannot be regenerated into
hybrid organisms. human races, somatic cell
hybrids
Interrogation, Genetic: This is an in depth study of the
function of a gene or a group of genes.
Interrupted Mating: Bacterial conjugation is halted at
definite intervals (by stirring the culture) in order to
determine the order of gene transfer and establish the
map position on the basis of minutes required for
the transfer of a particular gene(s) from the donor to
the recipient. The interruption stops the transfer.
conjugation mapping
Intersectin: An endocytosis protein. endocytosis
Intersex: The true intersex types have both male and
female gonads which is a very rare condition. More
common types are those who have either female or
male gonads and chromosomal constitution but they
express, to varying degrees, the secondary sexual
characteristics normally unexpected for their chro-
mosomal constitution. The intersex phenotype is
determined by autosomal genes and in species where
the sex chromosome:autosome ratio determines
sexuality, the aneuploids appear as intersex types.
In Drosophila the tra (transformer, chromosome
345) homozygotes of XX chromosomal constitution
are sterile males. The tra2 (chromosome 270)
mutation in XX background has similar effects as
tra; in XY background the males look normal and
behave in a normal manner yet their sperm is not
motile. The dsx (doublesex, 348.1) locus has
numerous alleles. The homozygotes for their null
alleles (in either XX or XY background) and the
heterozygotes for the dominant alleles (in XX
background only) are intersexes. The ix gene
(intersex, 260.5) makes females intersex with
reduced male and irregular female external genitalia.
The ix/ix males appear to be normal but they are
mostly homosexual and the ix/ + heterozygotes court
females and young males but not adult males. The tra
and dsx genes regulate sex expression by alternative
splicing of the RNA transcript involved in normal
sexuality. In some insects, like the Gypsy moth
(Lymantria dispar) the sex-determining genes have
strong and weak alleles in some populations and
the crosses regularly yield intersex individuals. The
crosses between head lice (Pediculus capitis) and
body lice (P. vestimenti) produce intersexes in F
2
and
F
3
. Further, 98 to 96% of angiosperm plants are
hermaphroditic and among 2 to 4% dioecious species
intersexes occur, depending on the number of each of
the sex chromosomes they carry. In Melandrium, for
instance, the XXYand XXXYmales produce occasion-
ally intersex flowers but the XXXXY individuals
are hermaphroditic. hermaphroditism, pseudo-
hermaphroditism, sex determination, introns, gy-
nandromorphs, homosexuality, relative sexuality,
gonads, anti-Mllerian hormone, Lymantria for
photo, Vaiman D, Pailhoux E 2000 Trends Genet
16:488.
Interspersed Repetitious DNA: Describes nearly 35% of
the human genome, including various types of active
or inactive transposable elements. SINE, LINE,
redundancy
Inter-SS PCR: cancer
1016 Interpolation, Linear
I
Interstitial Segment: Refers to the chromosomal region
between the centromere and the translocation break
point. translocation
ELOD
1 2
1
_ _
n
2
log
1
1 p
_ _
Interval Mapping: Considers pairs of adjacent markers
and maximizing the likelihood of quantitatively
expressed gene loci (QTL) being in between. ELOD
is the expected lod score, = recombination fraction,
p = the proportion of variance contributed by QTL,
n = sample size. The calculation may be difficult
under practical conditions because there may be more
than one QTL per linkage group. An interval
mapping based on the least squares method may be
better. QTL, lod score, least squares, ASP
analysis; Ott J 2001 Advances Genet 42:125.
Intervarietal Substitution: This is basically similar to
alien substitution except the chromosomes belong to
different varieties of the same species. alien
substitution
Intervening Sequence (IVS): intron
Intimate Pairing (synapsis): Refers to the very close
apposition of the chromosomes at the meiotic
prophase that makes possible crossing over (gene
conversion) and recombination. recombination
mechanisms eukaryotes, recombination molecular
mechanisms prokaryotes, recombination models,
synapsis
Intimim: An enterobacterial protein that mediates the
attachment of the bacterium to the epithelial cells of
the intestine and causes erosion facilitating the
transport of proteins and intestinal inflammation as
a consequence of the infection.
Intine: Refers to the inner layer of the wall of the pollen
grain.
Intrabody: An antibody expressed by intracellular
immunization in the target cells. intracellular
immunization, gene therapy, tumor vaccination;
Duff RJ et al 2000 Methods Enzymol 313:297.
intradiabody
Intracellular: This means located within a cell(s).
Intracellular Clock: The differentiation of particular
cells into a particular type of tissue during embryonal
development is controlled by the timing of the signal
received for differentiation. For exanple, an animal
epithelium excised at the gastrula stage grafted on to
the eye disc of an embryo may differentiate into a
neural tube but if the same tissue is grafted on to the
same position a few hours later it may differentiate
into an eye lens.
Intracellular Immunization: This involves the targeting
of the antibody to a specific cellular compartment.
This can be accomplished by signal peptide se-
quences specific for, say, the endoplasmic reticulum,
mitochondria, the cell nucleus, cytoplasm in general,
specific membranes, etc. The function of proteins at
the target sites may be modulated leading to alteration
of susceptibility to viral infection and replication,
modifying cells surface receptors, altering light
receptors, affecting mitosis, etc. differentiation,
biotechnology, intrabody, Chames P, Baty D
2000 FEMS Microbiol Lett 189:1.
Intrachromosomal Gene Locus Association: inter-
chromosomal interaction
Intrachromosomal Recombination: May be responsible
for deletions and duplications. sister chromatid
exchange, transposition, ectopic recombination,
recombination intrachromosomal
Intraclass Correlation: A form of analysis of variance
used for the estimation of heritability on the basis of
variances between and within classes, e.g., in the
progeny of a larger number of different males mated
to a smaller number of females, each of which has
several offspring (see Table I5). Thus, the degree of
variance within the litter of a male mated (sired) to the
same female (within sires) can be compared to the
variance among the total offspring of individual
males mated to different females (between sires).
The intraclass correlation of the sires is 1/4 of the
heritability for the trait considered because each male
contributes half of the genetic material to the
offspring quantitatively analyzed, and these again
contribute only half of their chromosomes through
their haploid sperm. The procedure of calculation is
illustrated by the hypothetical example given here.
ANALYSIS OF VARIANCE
df SS MS
Between Males SS
S
3 6:5 2:17
Within Males SS
P
20 21:5 1:075
^
2
S
MSSMSP
n
i

2:171:075
6
0:1825 (the males
variance component) ^
2
p MSP 1:075 (the
progeny variance component)
The Males Intraclass Correlation (r
1
), ^
2
S
/(^
2
S
+
^
2
P
) is equal to 1/4 of the heritability, hence h
2
= 4^
2
S
/
(^
2
S
+ ^
2
P
) = 4[0.1825/(0.1825 + 1.075)] = 0.58.
correlation, heritability, variance, variance
analysis. (Heritability is denoted by h
2
for historical
reasons but it is not the second power of an entity).
(See Hill WG, Nicholas FW 1974 Biometrics
30[3]447).
Intraclass Correlation 1017
I
Intracytoplasmic Sperm Injection: ICSI
Intradiabody: This is an intrabody with dual specificity,
i.e., targeting two receptors within a pathway such the
VEGF receptor and the Tie-2 receptor, and it leads to
increased anti-tumor effect (Jendreyko N et al 2005
Proc Natl Acad Sci USA 102:829). intrabody,
VEGF
Intrafallopian Transfer: This transfer of gametes (GIFT)
or zygotes (ZIFT) is involved in infertility treatment
procedures whereby the spermatozoa and the mature
oocytes or in vitro generated zygotes, respectively are
surgically inserted into the fallopian tube of the
female where fertilization and/or segmentation may
proceed. These procedures have a higher rate of
success for conception than in vitro fertilization but
they often lead to twinning if more than a single egg
or zygote is used. ART, in vitro fertilization,
TET, PROST; Klonoff-Cohen H et al 2001 Fertil
Steril 76:675.
Intragenic Recombination: This is rare because alleles
of a locus are very close to each other. Intragenic
reciprocal recombination is expected to yield wild
type and double mutant recombinants that can be
verified only if flanking non-allelic markers are
available. These outside markers ideally should
not be more than 510 map units at both sides of the
locus. The mutant alleles are m
1
, m
2
and m
3
,
respectively, p, t and an are outside markers. The +
sign indicates non-mutant (see Fig. I47). The
following crosses are required to determine the linear
order of the m alleles in a simple case:
Among the recombinants, the m phenotype in-
dicates double recessive alleles in the same strand
whereas the m
+
phenotype is an indication of
recombination between two recessive alleles present
in the heterozygous parent, which is testcrossed.
According to these results the order of the mutant
alleles andthe markers must be p- m
3
- m
1
- m
2
- t -aand
none of the recombinant classes are supposed to be
contaminants because the markers are consistent with
the recombination events suggested. The double
Table I5. Procedure for calculating heritability based on intraclass correlation. The mean scores of the offspring
are represented in the body of the table. (Y stands for individual or group measurements)
Males A B C D
Females Yi (Yi
)
2
Yi (Yi
)
2
Yi (Yi
)
2
Yi (Yi
)
2
E 2 (4) 3 (9) 3 (9) 4 (16)
F 3 (9) 2 (4) 4 (16) 3 (9)
G 3 (9) 3 (9) 4 (16) 2 (4)
H 4 (16) 2 (16) 3 (9) 4 (16)
I 3 (9) 4 (16) 4 (16) 6 (36)
J 5 (25) 2 (4) 5 (25) 5 (25)
Sum Y
i
20 16 23 24
Sum Y
i
2
72 46 91 106
Sum () all Sum () all n (all measurements) = 24,
Y
i
= Y... = 83, Y
i
2
= 315, n
i
(no. of families of females) = 6
Correction factor (C) = Y
2
... / n = 83
2
/24 = 6889/24 = 287
Uncorrected Sum of Squares (Y
i
2
/n
i
)
= (20
2
+ 16
2
+ 23
2
+ 24
2
)/6 = 1761/6 = 293.5
Sum of Squares Between Males = SS
S
= (Y
i
2
) C
= 293.5 287 = 6.5
Sum of Squares Within Males = SS
P
= Y
i
(Y
i
2
/n
i
)
= 21.5
Mean Square (MS) is SS/df
(The lower index S stands for sires; the lower index P is for progenies)
1018 Intracytoplasmic Sperm Injection
I
mutant recombinants may be further tested by
recombination to yield the two mutant classes.
Intragenic recombination is a rare event (0.02 to
0.000001 or less), close to the range of mutation
frequency. Intragenic recombination is more likely to
preserve protein function than random mutation
(Drummond DA et al 2005 Proc Natl Acad Sci USA
102:5380). (See Whittinghill M 1950 Science
111:377).
Intragenic Suppressor: suppressor gene
Intrasteric Regulation: The internal sequences of protein,
resembling substrate tracts (pseudosubstrate) act di-
rectlyat the active site incontrast tothe allosteric effects
when the allosteric molecule bears no similarity to the
substrate and attaches to the protein at a site different
from the active site. Intrasteric control is a means of
autoregulation. allosteric control, autoregulation;
Kobe B et al 1997 Adv Second Messenger Phospho-
protein Res 31:29.
Intrauterine Fertilization (IUI): In this process the
sperm is deposited directly into the uterus, bypassing
the cervix (the anterior part of the uterus, which may
form a barrier to the passage of the sperm). This type
of medical intervention may be undertaken to treat
infertility in humans. ART
Intravasation: Refers to the entrance of an extraneous
substance into the blood vessels. Metalloproteinases,
receptor urokinase plasminogen activator (uPA) and
their inhibitors may affect the process. Metastasis
of cancer cells may depend on intravasation.
extravasation, metastasis, metalloproteinases,
urokinase
Intrinsic: This adjective defines the basic, essential
attribute of a phenomenon. extrinsic
Intrinsic Disorder: Proteins have multiple conforma-
tions. They may play a regulatory role by optimizing
allosteric couplings with different ligands (Hilser VJ,
Thompson EB 2007 Proc Natl Acad Sci USA
104:8311). allostery
Intrinsic Rate of Natural Increase: age-specific birth
and death rates
Intrinsic Terminators: These terminators of transcrip-
tion in prokaryotes do not require co-factors (are rho-
independent) for the termination of transcription.
transcription termination in prokaryotes
Introgression: Refers to the transfer of genes from one
group of species to another. The two populations may
inhabit the same area (sympatric) or they may have
only occasional contact because of being in different
areas (allopatric). After the initial crossing the mating
continues largely within the group and therefore only
a few of the borrowed genes are maintained.
Marker-assisted introgression uses molecular tools to
monitor the transfer/presence of the desired genetic
regions, especially for quantitative trait loci. In
human populations mitochondrial DNA analysis
and Ychromosomal haplotyping are especially useful
for tracing the ethnic origins. QTL, marker-
assisted selection, speciation, co-evolution;
Anderson E 1949 Introgressive Hybridization, Wiley,
New York, Saetre GP et al 2001 Mol Ecol 10:737.
Introgressive Hybridization: This accomplishes intro-
gression. introgression
Intron Homing (retrohoming): Refers to the process of
insertion of an intron at a particular site within an
intron-less cognate sequence. Accordingly, some
introns of yeast mitochondria serve as mobile genetic
elements besides performing a ribozyme function.
The homing introns, mitochondrial or nuclear, are
endonucleases with similarities to restriction en-
zymes but their recognition sequence is much longer.
Intron homing may utilize either (i) the double-
strand-break repair pathway common in genetic
recombination and yielding reciprocal crossover
and non-crossover products, or (ii) a synthesis-
dependent strand annealing process that does not
produce flanking crossing over. introns, ribo-
zyme, homing endonuclease, mtDNA; Mohr G
et al 2000 Genes, Development 14:559; Belfort M
et al 2002 in Mobile DNA II, ASM Press,
Washington, DC p. 761.
Intron Retention: Refers to a failure of splicing out an
intron. introns, splicing, alternative splicing
Intron Sliding: This is an alternative type of splicing
used by cryptic splice sites generally caused by the
presence of SINE elements. splicing, alternative
splicing, SINE, introns; Rogozin IB et al 2000
Trends Genet 16(10):430.
Test crosses
X
p m
1
t
+
a
p
+
m
2
t

a
+
p
+
m
3
t
+
a
p
+
m
2
t

a
+
p m

t

a
p m

t

a
p m

t

a
+
and p
+
m
+
t
+
a
p
+
m
+
t
+
a

and p

m

t

a
+
p m
+
t

a
+
and p
+
m

t
+
a
Reciprocal recombinant phenotypes
p m
1
t
+
a
p
+
m
3
t

a
+
X
X
p m

t

a
p m

t

a
p m

t

a
p m

t

a
Figure I47. Intragenic recombination test
Intron Sliding 1019
I
Intron Slippage (intron sliding): The position of introns
(intronexon boundary) may vary among homolo-
gous genes of evolutionarily related species by one or
a dozen or more nucleotides. introns, alternative
splicing; Wistow GJ, Piatigorsky J 1990 Gene
96:263.
Intronless Paralogs: These are genes inserted into the
genome by retrotransposition of processed mRNA.
retrotransposon, processed gene; Schimenti JC
1999 Mamm Genome 10(10):969.
Introns: These are nucleotide sequences within a gene
that are not represented in the mature mRNA
transcripts of that gene (intervening sequences, IV).
Introns are transcribed but not translated into protein
that would be part of the products of the exon-coded
genes or will not be included into the final RNA
encoded by the gene. Introns separate the coding
sequences of the exons (see Fig. I48). Introns are seen
in the majority of the eukaryotic genes, including
genes of mitochondria and chloroplasts and also in
viruses of eukaryotes but they are exceptional in
prokaryotic genes. In land plant plastid DNA ca. 20
introns are present and their size varies from 400 to
over 1000 bp. The average size of an intron in mice is
around 1,800 300 and in humans about 3,000 550.
In the X chromosome the intron size is substantially
longer. In imprinted genes the intron number, and
particularly its size, is smaller. The RNA maturases in
mammals are actually intron sequences within protein
genes and assist the splicing of the pre-mRNA
transcripts. In algae the cpDNA introns are quite
variable in number and size; in Euglena 149 introns
have been detected. In the red alga Porphyra no
introns in the cpDNA have been observed. In
Chlamydomonas the insertion site of an intron
corresponds to an E. coli rRNA domain. Introns
may appear as latecomers to the eukaryotic organelle
genes since in multiple evolutionary lines they are
non-homologous either by sequence or location.
However, the thymidylate synthetase gene of T4
bacteriophage has an intron, and the archaebacterial
tRNA
Leu
as well as the large ribosomal subunit genes
have introns. One of the largest introns (64-kb) has
been found in the human thyroglobulin gene which is
involved in the regulation of energy metabolism and
in the various forms of goiter. The overall profile of a
gene can be represented as:5- Enhancer-promoter -
transcription initiation site - leader - exon intron
exon-termination signal - 3.
The origin of introns is unclear. Some arguments
favor their ancient evolutionary presence, preceding
the divergence of eukaryotes from prokaryotes
(Fedorov A et al 2003 Genome Res 13:2236). Some
introns may be located at critical regions of the gene,
dividing it into functional domains or separating
-helices from -sheets. It has been suggested that
increased replication rate is inversely proportional to
the number of introns. Indeed, introns are rare in
prokaryotes and fewer in yeast.
Introns may regulate genes controlling complex
developmental pathways (Juneau K et al 2006
Genetics 174:511). The large homeotic genes of
Drosophila seem to contain more introns than other
simple genes. The greater density of introns within
genes may be promoted by sexual reproduction that
enables themto propagate in a selfish manner through
gametes of both parents. Introns can protect against
the deleterious consequences of recombination
because if this occurs within introns rather than
within exons, no harm can be caused to the coding
capacity. Recombination frequency is negatively
Structural Gene Sequence
7.7 Kbp
Genomic DNA
1
1
2
2 mRNA
3
3
4
4
5
5
6
6
7
7
A
B
Intervening Gene Sequence Flanking Gene Sequence
Figure I48. (Photomicrograph is by Batosin, L., Laub, O. Horouritz, M. & Y. Aloni. Courtesy of Professor Aloni.)
1020 Intron Slippage
I
correlated with intron length. Introns can also protect
against illegitimate recombination by interrupting
homologous tracts at random sites. Although these
problems have not yet been resolved, the mechanics
of transactions concerning introns has made substan-
tial progress.
The number of introns varies greatly (Llopart A
et al 2002 Proc Natl Acad Sci USA 99:8121). Some
genes, e.g., the histone, human and interferon
genes have no introns, whereas the interferon gene
has several. The large (2-Mbp) human dystrophin
gene contains over 60 introns. (Dystrophin is a
muscle protein, deficient in muscular dystrophy). The
average size of an intron generally varies between 75
and 2,000 bp but some introns are several times as
long or no more than about a dozen nucleotides.
There are no introns in the 5S, 5.8S, U RNA, 7SL and
7SK RNA genes. In organisms with compact
genomes like Drosophila and budding yeast the
number of introns is usually small but fission yeast
contains a large number. Introns comprise nearly 24%
of the human genome. The average number of
introns/gene in humans is about 7. Interestingly, the
mitochondrial genes of budding yeast have relatively
more introns than the nuclear genes.
Introns are removed from the primary transcripts of
the genes during processing. The removal of introns
is essential for the expression of genes. Group II
introns have six domains; domain 1 (D1) and D5 are
essential for splicing. Thus, the mRNA becomes
shorter than the primary transcript. When the mRNA
is hybridized to the genomic coding strand of DNA,
the latter reveals loops at those positions in the
mRNA from where the introns were removed. The
chicken ovalbumin gene contains seven introns
and loops corresponding to their location and length
can be detected by electron microscopy (see map
by Dugaiczyk et al Stadler Symp. 11:57, and
interpretative drawing by Rdei, 1982). Alternative
mRNAs can be obtained from the same DNA
sequence by controlling the length, number or pattern
of exons used, depending on (i) the site of initiation of
transcription, or (ii) the alternative sites of poly-
adenylation signals, or (iii) the selective retention of
particular exons in the mRNA. By using these
mechanisms the products of single genes can be
diversified during development or differentiation.
Alternative splicing may be accomplished by using
more than a single promoter, resulting in alternative
long or short transcripts, depending on the site of
transcription initiation. Alternative polyadenylation
signals, at more than a single location downstream,
may truncate the transcript at the 3 end. An example
of mechanism (see Fig. I49) (i), alternative promoters
the exons are bracketed, introns are in bold numbers
and parenthesis. Alternative splicing occurs in
various eukaryotic genes and various viruses of
eukaryotes. In the small genomes of the latter systems
a single transcript may permit the production of
several proteins. In the determination of correct
splicing both cis- and transacting proteins cooperate.
When the introns are removed the exons are spliced
together and the continuity of the mRNA is restored.
There are two splice sites, the upstream donor site
and the downstreamacceptor site. When the invariant
bases (shown in bold numbers in the example) are
altered, splicing generally fails.Other neighboring
bases may also affect the efficiency of splicing. In
animal nuclear genes, an A residue in the vicinity of
the splice site is required but its position does not
have to be absolutely fixed relative to the splice site.
In yeast, there is an absolute requirement for
a conserved UACUAAC tract within 6 to 59
nucleotides upstream from the 3 splice signal. Some
Figure I49. Splicing mechanisms
Introns 1021
I
genes have more than one splice site pairs which
facilitate alternative splicing and the assembly of
different mRNAs. Although originally introns were
regarded as junk DNA, it is now known that some
introns are translated but have independent functions
from the exons; some have a role in the processing of
the transcript shared by the neighboring exons
whereas others perform regulatory functions (see
Figs. I50 and I51).
On the basis of structural information about the
splice sites, some special introns have been classified
into group I and group II (see Table I6). The principal
characteristics of group I introns are (i) their splicing
does not always require a protein enzyme, rather (ii) a
short internal sequence facilitates their folding and
splicing that is initiated by (iii) an extraneous
guanosine or a phosphorylated formof it (see Fig. I52).
Group II introns do not have conserved internal
sequences yet they are capable of foldback pairing
and the splicing requires an intrinsic signal rather than
an extraneous guanine. The spliced group II introns
forma lariat (similar to that of a tethering rope), the 5
P end forms a phosphodiester bond with the 2-OH
group of a nucleotide within the chain at some
distance. The loop itself may have three nucleotides
(GpApA).
The splicing of group I introns requires transest
erification (phosphodiester linkage ex-changes).
Transesterification takes place without severing the
bonds first. The self-splicing is mediated by ribo-
zymes, RNAs that have enzyme-like catalytic func-
tions.
Ribozymes facilitate the formation of the proper
configuration of the RNAtranscript and may function
like endonucleases. The aI2 ribonucleoprotein of the
COX1 yeast mitochondrial gene catalyzes the cleav-
age of the DNA target, recognized by complementar-
ity of the sequences within the intron RNA. After
cleaving the DNA the aI2 protein reverse transcribes
the intron RNA using the 3 end of the DNA as a
primer. The aI2 RNA cleaves the sense strand of the
DNAwhereas the aI2 protein cuts the antisense strand
and the latter also boosts the activity of the aI2
ribozyme. The intron assumes a complex secondary
2 OH
Lariat
intron in the RNA
5 P
2 O
2-5 phosphodiester bond in the lariat
X-O-p-X-Op-X-O-p-X-O-p
59P-X-O-p-X-O-p-X-O-p-X-O-p-X-O-p-X-O-p-X-OH
Figure I50. Lariat formation
5
3
5-exon
exon-3
3
1
2
3
3
exon-U
Guanosine
UpA
pA
O
O NUCLEOPHILIC ATTACK
spliced exon 5
exon 3
INTERNAL SEQUENCES GUIDING
THE FOLDING OF THE TRANSCRIPT
INTRON
H
GpU-exon
GpU
G-3
UpU
intron
intron
P O
O
A
O

5
Figure I51. Self-splicing steps. Self-splicing of a group I intron (1) a guanosine (or guanylic acid) conducts a nucleophilic
attack against a phosphate group near the point of juncture, and transesterification follows later at both 5 and 3 junctions.
this is accompanied by the recognition of internal sequences that guide the folding. (2) exon termini in bold and the
ends of the intron is in outline letters. (3) spliced exon and intron are displayed
1022 Introns
I
structure by base pairing of some complementary
sequences separated by non-pairing tracts. The
extraneous guanosine launches a nucleophilic attack
(an electron-rich molecule reacts with an electron
poor one that is willing to accept electrons) at the
exon-intron boundaries resulting in a nucleotide
chain breakage at the site and an exclusion of the
intron. Not all group I introns are able to self-splice
without the help of maturase proteins encoded by
introns within some yeast mitochondrial genes. The
self-splicing of group II introns is somewhat similar
to that of group I. In group II there is no involvement
of guanine. The 2 -OHgroup of an adenine within the
intron initiates the nucleophilic attack. After appro-
priate folding to bring the 5 and 3 junctures in
proximity to each other, the exon is spliced by
transesterification and the intron is released as a lariat.
The primary RNA transcript of nuclear pre-mRNAs
is capped. Cleavage takes place at the 5 end of the
intron upstream of a pGU pair as indicated by the
arrow. The free 3 end of the intron forms a lariat with
an internal A residue and then the intron with the
lariat is released and the 3 end of the first exon is
ligated to the 5 end of the next exon. The outcome is
Table I6. The intron - exon border sequences are conserved within groups of different classes of rna transcripts
(after cech, cell 44: 207) the bold letters indicate constant bases, the indicates splice sites, py stands for any
pyrimidine and pu for any purine and x means any base
INTRON 5 SPLICE JUNCTION 3 SPLICE JUNCTION
Common nuclear pre-mRNA CPuG GU
G
U
AGU (PY)
n
AG X
Yeast nuclear pre-mRNA GUAUGU (PY)
n
AG X
tRNA X X X X
1
Introns Group I U G
2
Introns Group II GUGCG (Py)
n
AU
Euglena plastid mRNA GUG
U
C
G (Py)
n
A
C
U

1
Nuclear rRNA genes of in some lower eukaryotes, mitochondrial and plastid rRNA genes
2
Yeast mitochondrial genes for cytochrome oxidase and cytochrome b
Proteins
Proteins
EXON 1
EXON 2
EXON 1
EXON2 AGGU
SPLICED EXONS
INTRON
INTRON
GA AC AU CAU
: pseudouridine; A
m
, U
m
: methylated bases
AGGUAAGU
mRNA
5 splice
3 splice
5
5-AAGU AG-3
3
Figure I52. The U1 and U2 snRNAs facilitate the proper configuration of the folding of the transcript and thus identify the
correct splicing sites. The A-2OH nucleotide leads the nucleophilic attack, which is followed by transesterification and
ligation of the exon
Introns 1023
I
the same as discussed earlier. The splicing of the
nuclear pre-mRNAs requires, however, a more
complex machinery involving spliceosomes.
The spliceosomes are assembled from short U-rich
RNAs, ranging in size from 65 (U7) to 217 (U3)
nucleotides and a set of different proteins. The most
common U RNAs in the mammalian nucleus are U1,
U2, U4 and U6. The U3 RNA is involved in RNA
processing in the nucleolus. The U7 RNA assists in
the formation of the 3 end of the histone mRNAs that
have no introns. The corresponding U RNAs are
highly homologous even among taxonomically
different organisms such as humans and dinoflagel-
lates. The homologous U RNAs among vertebrates
are almost identical (ca. 95% similarity). The
spliceosomes contain a common set of seven proteins
(generally designated by capital letters [B, A, etc.] or
by molecular weight [e.g., 59K, 25K]) and may also
contain a few specific proteins. About 1% or less of
the introns uses AU and AC (rather than the more
common GU and AG) as terminal nucleotides. In
plants (crucifers) especially AU-AA introns may
occur. Some of these introns also use the U12 snRNA
for processing. The intron-encoded U22 small
nucleolar RNA facilitates the processing of the 18S
ribosomal RNA in Xenopus oocytes. The U1 snRNA
specifically binds to the 5 splice site of the intron and
protects this region from RNase attack but it does not
cleave at the splice site. The U2 snRNA complex
performs the same function near the 3 end of the
intron around the adenosine residue whose 2-OH is
involved in the formation of the lariat. The spliceo-
somes are ellipsoid complexes (about 25 50-m in
size) that actually bring together the splicing sites to
make the cut and paste process possible. These
bindings generally require some degree of comple-
mentarity but that is not complete. Besides these two
spliceosomes, others (U2, U4, U6) and a number of
binding proteins may be involved in facilitating and
stabilizing the binding.
The position of introns in tRNA genes is located
next to the third (3) base of the anticodon triplet,
with a single base in between. Yeast has about 40
nuclear-coded tRNAs and 10% of them have a single
intron containing between 14 and 46 bases. This
regular location is somewhat enigmatic because
tRNA
Tyr
genes of yeast with deleted intron sequences
are still transcribed, processed normally and function.
In the primary transcript, the intron has a triplet that is
complementary to the anticodon. For correct splicing,
the various loops and arms of the tRNA cloverleaf are
important. The first step in splicing of tRNA
transcripts is a cleavage by an endonuclease at the
ends of the intron. In yeast the 5 terminus of the exon
is then represented by an OH group and the 3
terminus by a 2,3-cyclic phosphate. The cyclic
phosphodiesterase then breaks the ring and generates
a 3-OH and a 2-O-(PO
3
) terminus. The 5-OH end
is phosphorylated by a kinase, requiring ATP. Thus,
the termini are ready for joining by an RNA ligase
enzyme. Essentially similar reactions are observed in
splicing nuclear tRNAs in mammals and plants.
The splicing mechanisms shown and discussed
earlier involve splicing exons within the same
primary RNA transcripts. In some instances exons
originally located in different transcripts, even in
different chromosomes, may be spliced by transspli-
cing (see Fig. I53). Transsplicing can generate.
mRNAs from leader sequences remote to the
exons. Transsplicing is common in the protozoa,
Trypanosomes where different exons can be joined to
a single 35-bp leader sequence. (The exons are
scattered among approximately 100 chromosomes).
The 3 end of the leader and the 5 end of the coding
exons can be joined. Since the 5 end of the intron
carries the generally conserved 5-GU sequence, the
remote other intron, preceding the remotely tran-
scribed coding exon, terminates at 3 with the
conserved AG bases and also has an adenosine
nucleophile somewhere in the vicinity of its 5
terminus. The two originally remote introns can be
brought together by a 5 to 2 bond as a branched
molecule, and subsequently both introns are eliminated
and the leader is joined to the coding exon as outlined
in the Fig. I53. Transsplicing also occurs in other
eukaryotes, e.g., in the nematode Caenorhabditis
leader
leader
exon
leader exon
exon
branched intermediate
juncture and elimination of introns
intron 1
GU AG
AG
UG
A
A
intron 2
Figure I53. Transsplicing
1024 Introns
I
elegans andinthe chloroplast genes of plants. The open
reading frames of class II introns have sequences
reminding to reverse transcriptases of the type of
retroposons. There is no evidence, however, that these
would function as reverse transcriptases. Introns and
spliceosome sites showevolutionary variations and are
suitable for tracing phylogenetic relationships (Roy
SW, Gilbert W 2006 Nature Rev Genet 7:211). The
map position of introns in animals, plants and fungi
shows considerable alignment and indicates that the
ancestral introns predate the evolutionarydivergence of
these taxonomic categories (Fedorov Aet al 2002 Proc
Natl Acad Sci USA 99:16128). Among 10,020 intron
positions in humanmouse comparisons, five cases of
intron loss were detected in the mouse evolutionary
lineage but not in humans; moreover no gain was
observedineither lineage (RoySWet al 2003Proc Natl
Acad Sci USA 100:7158). Intron loss is attributed to
recombination of reverse transcriptase products of
spliced mRNA, processed genes (Roy SW, Gilbert W
2005 Proc Natl Acad Sci USA 102: 713). In seven
diverse eukaryotic groups intron loss varied from2
10
9
to2 10
10
per year duringevolution and the rates
of gain were between 6 10
13
and 4 10
12
. These
figures indicate that the early ancestors of eukaryotes
were intron-rich rather than introns being of more
recent origin because the gain was much less frequent
than the loss (Roy SW, Gilbert W2005 Proc Natl Acad
Sci USA 102:5773). Single introns in the majority of
species tend toward the 5 end; Arabidopsis is an
exception (Sakurai Aet al 2002Gene 300:89). Group II
introns can be targeted for insertion into a 14-
nucleotide region of target DNA of prokaryotes.
Introns inserted in the antisense orientation cannot
splice and disrupt the gene. Introns inserted in the sense
orientation may serve for selective regulation of gene
expression when linked to inducible promoters.
A comparison with the orthologous regions in the
mouse and the chimpanzee reveals that human introns
with the most similar boundaries are younger. Human
introns are alternatively spliced with exceptionally
high frequency. Genomic duplication has been an
important mode of intron gain in mammals. The
alternative splicing of transcripts containing these
intron-breeding repeats may provide the plasticity
required for the rapid evolution of new human
proteins (Zhuo D et al 2007 Proc Natl Acad Sci
USA 104:882).
transcription, ribozymes, endonuclease, li-
gase, branch point sequence, intron group III,
mtDNA, RNA maturase, speckles intranuclear,
spliceosome, exon junction complex, spliceo-
somal intron, SR motif, Neurospora mitochon-
drial plasmids, intein, snoRNA, deadbox
proteins, DEAH box proteins, splicing, gene,
alternative splicing, TAP, processed gene,
homing endonucleases; Bassi GS et al 2002 Proc
Natl Acad Sci USA 99:128; Clark F, Thanaraj TA
2002 HumMol Genet 11:451; origin and evolution of
introns: Roy SW, Gilbert W 2005 Proc Natl Acad Sci
USA 102:1986, self-splicing ribozyme-like introns:
Nielsen H et al 2005 Science 309:1584; http://hsc.
utoledo.edu/bioinfo/eid/index.html, spliceosomal in-
trons: http://genome.imim.es/cgi-bin/u12db/u12db.
cgi.
Introns Group I: These self-splicing introns in some
ribosomal genes use mechanisms different from the
pre-mRNA or the majority of tRNA genes. introns
for characterization, mitochondrial genetics for
introns as mobile elements and plasmids, spliceo-
somal introns, structure: Adams PL et al 2004 Nature
[Lond] 430:45.
Introns Group II: These introns are large ribozymes in a
few mitochondrial, chloroplast, fungal and bacterial
genes and differ in structure and splicing mechanisms
from the common introns (Type I) of eukaryotes.
Mobile group II introns are retroelements with
reverse transcriptase activity. They are also self-
splicing and are capable of intron homing. Group II
introns can cause insertional mutations. Both group I
and group II introns require deadbox proteins as RNA
chaperones (Huang H-R et al 2005 Proc Natl Acad
Sci USA 102:163). introns, intron homing,
mitochondrial genetics, spliceosomal introns,
deadbox proteins, chaperone, intron group III,
Lambowitz AM, Zimmerly S 2004 Annu Rev Genet
38:1.
Introns Group III (twintron): These are relatively short,
group III introns inserted within the boundary of
group II introns in the cpDNA of Euglena. Some
bacteria also have twintrons in intergenic regions.
ctDNA
Intususception: Refers to the insertion of interstitial
tissue into the lumen of existing vessels.
Inulin (fructan): This denotes one of the many types of
polymers of (3040) fructose units in plants (see
Fig. I54).
Invader: This refers to a molecular procedure for DNA
and RNA quantification. It is suitable for highly
sensitive discrimination between mutant and wild
type forms and SNPs. The modified invader assay is
suitable for the detection of microRNA precursor and
microRNA in unfractionated detergent lysate using
fluorescence analysis on microtiter plates (Allawi HT
et al 2004 RNA10:1153). (See Kwiatkowski RWet al
1999 Mol Diagn 4:353; Olivier M et al Nucleic Acids
Res 30[12] e53)
Invader 1025
I
Invagination: Refers to folding inward (see Fig. I55).
Figure I55. Invagination
Invariance: This is the reciprocal value of the variance.
variance
Invasin: This is the integrin-binding protein of Yersinia
bacteria assisting infection. integrins, Yersinia
Invasion of DNA Strands: branch migration, Holli-
day model
Invasive: Refers to the penetration of cells commonly
leading to their destruction. Can also indicate
migration of cancer cells. metastasis, RAGE
Invasive Growth: Yeast cells do not stay on the surface of
the culture medium but penetrate it in search of
nutrients.
Inverse PCR: inverse polymerase chain reaction
Inverse Polymerase Chain Reaction: This process can be
used for molecular analysis of flanking regions of a
target (see Figs. I56 and I57).
Figure I56. Restriction fragment including flanks and
target
Figure I57. Head to tail association of the flanks in
inverse polymerase chain
The fragment shown here is circularized by its
cohesive ends and cut with a restriction enzyme
within the target. As a consequence a head-to-tail
association of the flanks is produced:
This head-to-tail sequence of the flanks is amplified
by PCR for ucleotide sequencing. The two flanks
may be separated if an appropriate restriction
endonuclease site is known at or near their boundary.
PCR, target, tail-PCR, capture PCR [CPCR]
Inversion: A chromosomal segment is turned around by
180(); centromere (see Fig. I58).
Such chromosomal rearrangements require two
breaks, both of them in one chromosome arm in the
case of paracentric inversions, and one in each arm
across the centromere in the case of pericentric
inversions. Pericentric inversion may alter the arm
ratio of the affected chromosome as discussed earlier.
Within a single chromosome there may be more than
one inversion. These multiple inversions may be
independent or may be overlapping or a shorter
inversion may be included within a longer one.
If the chromosomes are well suited for cytological
analysis, the various types can be identified using a
light microscope (see Fig. I59).
Inversions as such may not have much phenotypic
consequence, unless they cause position effect,
influence the expression of the gene because they
interrupt either the coding or the non-translated
regulatory sequences. These effects may be serious
in the relatively rare inversion homozygotes. During
HOCH
2 O
O
O
O
n
O
O
H
H
H
H
H
H
H
H
HO
HO
OH
OH
O
H
H
H
HO
OH
OH
OH
OH H
H
H
HOCH
2
CH
2
OH
CH
2
CH
2
HOCH
2
HOH
2
C
Figure I54. Inculin
Figure I58. Paracentric and pericentric inversion
1026 Invagination
I
the early years of genetics, inversions were thought to
be C factors, crossing over inhibitors. Inversions
inhibit crossing over in inversion heterozygotes only
in the vicinity of the breakage points where the
rearrangement prevents intimate pairing of the
chromatids. Crossovers are not observed primarily
because the strands involved in recombination are
usually not transmitted through the paracentric
inversion females thus they do not produce defective
gametes (see Fig. I60). The consequences for the
sperms are not the same for paracentric inversion
heterozygotes because the microspore tetrad is not
linear and the crossover chromatids are not tied by the
inversion-bridge in such a way that they would not be
included in any microspore. Therefore in males all
four products of meiosis could potentially be
transmitted, however 50% of the gametes are still
defective. In pericentric inversion heterozygotes
duplication-deficiency gametes are formed (without
a bridge) in both females and males if crossing over
takes place within the inverted segments during
meiosis. Thus, crossing over may occur but the
crossover gametes or zygotes may not be viable. In
animals the consequence of duplication-deficiencies
may be different from that in plants. In plants the
defective gametes are usually prevented from fertili-
zation because of inviability, whereas in animals the
defective sperm may be capable of fertilization but
the offspring resulting from such a mating may not
survive. The cytological consequences of crossing
over within inverted chromosome segments are
diagramed and shown by a photomicrograph. Cross-
ing over within pericentric inversions has the same
genetic consequence as that seen in paracentric
inversions, namely 50% of the gametes formed by
meiocytes, which have suffered recombination are
duplication-deficient. In other words,, some of the
genes are present in the same strand twice and others
are entirely absent, and are therefore generally
inviable. Inviability may be gametic or zygotic. In
the gametophytes of plants the former is seen whereas
in animals the latter is prevalent. Crossing over in
pericentric inversion heterozygotes cytologically
differs from that in paracentric inversions (see
Fig. I61).
In the former, dicentric chromosomes and acentric
fragments are not generated by recombination.
Double crossing over within the same inverted
paracentric segment, involving two homologous
chromatids does not produce defective gametes (see
Fig. I62). Three-strand double crossing overs yield
both acentric fragments and dicentric chromosomes
besides the two parental ones. Four-strand double
crossing over results in the formation of two acentric
fragments and two dicentric chromosomes and
generally all gametes become defective. Paracentric
inversions may play an important role in speciation
because they may cause hybrid male sterility and
hence partial sexual isolation. W.S. Stone has
estimated that during the evolution of approximately
2,000 species of Drosophila, about 350 million
paracentric inversions might have occurred, and from
these tens of thousands have been permanently fixed,
and the fate of another similar number is still
undecided. Pericentric inversion may also play a role
in speciation because of the complete sexual
isolation, and the preservation of the inverted
segment as supergenes, refractory to recombination.
The descendence of inverted chromosomes in natural
populations can be determined on the basis of banded
chromosomes or restriction fragment patterns
(RFLP). It was found that in Drosophila subobscura
populations global climate warming increased the
frequency of inversions (Balay J et al 2006 Science
313:1773).
The frequency of inversions in human populations
is less than 1%per birth. The actual rate of occurrence
may be much higher because many of the afflicted
fetuses are spontaneously aborted. Inversions have
been added to various mutation tester strains of
Drosophila so that new mutations could be identified
within a particular chromosome without confounding
the results by recombination because inversions
eliminate the crossovers. Short inverted nucleotide
repeats are found at the termini of insertion/
transposable elements. Inverted duplication of nucle-
otide sequences form palindromes and facilitate the
formation of double-stranded sequences in single-
stranded nucleic acid chains and have determining
Figure I59. Two-strand paracentric inversion heterozy-
gote displays double chromatid bridge and two chromatid
fragments because of the chromatid tie keeps the
crossover chromatids in the middle of the cell, they fail
to be incorporated into the egg and thus prevent female
sterility. (Courtesy of A.H. Sparrow)
Inversion 1027
I
roles in conformation of the molecules, such as
in tRNAs. Evidence obtained from Drosophila
buzzatii indicated that inversions may arise by
recombination either within the target site duplica-
tions or between two copies of the hobo transposable
element. Chromosomal (DNA) inversions would be
expected to produce retro-proteins with an altered
three-dimensional structure. The stability of these
retro-proteins may or may not differ from the natural
sequence and may or may not affect the function
of the proteins. In case a foldback-like transposon
Kepler is inserted at inversion break points in
Drosophila buzzatii it leads to a substantial reduction
in gene expression supposedly due to the antisense
RNA effect (Puig M et al 2004 Proc Natl Acad Sci
USA 101:913).
a
a
a
a
d
b
b
b
d
a
a
d
c
b b
c
b c d
A
A
A
B
D
c
d
C
C
C
B
D
D
C

B

D
D
B
B
D
B
C
c
A
B
C
D
C
Paracentric inversion heterozygote
Inversion
chromatid
Normal
chromatid
Pairing and crossing over
Gametes
b
a
b
c
d
d
c
a
Duplication
Meiotic anaphase I
Deficiency
Inversion
A
A
A
A
a
c
complete chromatin
Normal
complete chromatin
Bridge and
fragment
C
Dicentric
crossover
strand
Acentric
crossover
fragment
B D
Figure I60. Consequences of recombination. Paracentric inversion heterozygotes produce 50% defective gametes
when crossing over takes place within the inverted chromosomal segment. since the frequency of crossing over depends
on the length of the segment inverted frequency of the defective gametes varies from0 to 50%. At the top, an inverted and
a normal chromosome are shown. such chromosomes can pair only if the inverted strands form a loop and thus gene-by-
gene alignment becomes possible. The configuration of one inverted and one normal strand is shown on the second line at
left. in the center of that line the pairing and crossing over (() are diagramed. As a result of recombination, one of the
crossover strands becomes dicentric and deficient for marker (D) and duplicated for marker (A/a). The other crossover
strand becomes acentric and deficient for A/A and duplicated for D/d. At meiotic anaphase I, the crossing over results in a
chromatid bridge because the chromatids are tied together even when anaphase separation proceeds. The tie may either
hold together the crossover chromatids and they cannot reach either pole, rather they remain in the middle of the
metaphase plane or if the tie breaks, depending on the site of the breakage, additional duplication and simultaneous
deficiency may occur. In animals and plants, after recombination of paracentric inversion heterozygotes only a viable
(normal or inverted) chromosome enters the egg and thus female sterility is usually not observed. In males (where polarity
does not occur during gametogenesis), if recombination takes place within the inversion, 25%of the gametes contain only
normal chromosomes, 25% carry inverted chromosomes containing complete chromatin. In the remaining 50%
duplication-deficiency or deficiency of the genes is observed, and such gametes are generally sterile or result in embryo
lethality. Recombination in pericentric inversion heterozygotes does not result in dicentric bridge but half of both male and
female gametes may become defective.
1028 Inversion
I
A 900 bp inversion in human chromosome
17q121.31 displays two main variations, H1 and
H2. The H2 variant is very rare in Africa or East Asia
but its frequency in Europe is 20%. In the Icelandic
population it undergoes positive selection because
both female and male carriers have more children
than non-carriers and the recombination frequency is
higher in females (Stefansson H et al 2005 Nature
Genet 37:129). recessive lethal tests in Drosophila,
speciation, mutation chromosomal, unbalanced
chromosomal constitution, palindrome, confor-
mation, hybrid dysgenesis, antisense RNA,
transposon; Ranz JM et al 2001 Genome Res
11:230.
Inversion Loop: inversion
Inversion of Oligonucleotides: The linkages are 33 or
55 and have inverted polarity within the normal
nucleotide tract. They are extremely resistant to
exonucleases and have a longer half-life than normal
oligonucleotides yet they may not disturb the Watson-
Crick structure. These may be used for oligonucleo-
tide therapy.
Inversion, Paracentric: This involves only one arm of a
chromosome. inversion
Inversion, Pericentric: The inversion spans across the
centromere. inversion
Inversions in Phages and Bacteria: One group of
enzymes is invertases (transposases) mediating
inversions between the inverted terminal repeats of
transposable elements. The other group comprises
integrases. The inversion may affect an invertible
promoter or the entire gene. The invertase of phage
MU(gin) is positioned outside the inversible 3000-bp
G region flanked by 34-bp inverted repeats. In one
Figure I61. Pericentric invession heterozygotes and crossing over
Inversions in Phages and Bacteria 1029
I
orientation the host specificity genes Sv and U ()
permit the attachment of Mu to E. coli and when
inversion () takes place the phage can be adsorbed
to other host bacteria. A similar system has been
observed in the phase variation of Salmonella.
phase variation, transposase, resolvase; Roth
JR, Schmid MB 1981 Stadler Symp 13:53; Johnson
RC 2002 In: Craig NL et al (eds) Mobile DNA II.
Amer Soc. Microbiol. Press, Washington, DCpp 230.
Invertases: These are proteins (Cin, Hin, Gin) involved
in viral transposition and bear extensive homology
with the N-terminal domains of the resolvases of
transposons. In biochemistry the enzyme sucrase
which hydrolyzes sucrose to fructose and glucose is
also called invertase. Cin, Tn, resolvase
Invertebrates: These are animals without a spinal
column. genome size: http://www.genomesize.
com/statistics.php?stats=inverts.
Inverted Repeat: repeat inverted, direct repeat
Invertrons: These are linear mobile elements in
plasmids and mitochondrial DNA. It seems that
5-linked proteins encode DNA and RNA replication
and integration functions. Agrobacterium, trans-
formation genetic, Hermanns J, Osiewacz H D 1992
Curr Genet 22(6)491.
Involucre: Refers to a whorl of bracts around an
inflorescence. bract
Involution: Denotes a degenerative type of development
that is marked by a return to a more primitive or
inactive state.
Iodine Stain: For coloring starch (amylose) blue-black
is used, while amylopectin (dextrin) is colored
reddish-brown (iodine120 mg and potassium iodide
400 mg in 100 mL water).
Iojap(ij): Refers to nuclear mutations in maize located in
chromosomes 3L-90 (ij1) and 1L (ij2), respectively,
causing leaf striping because of defects in the
development of plastids. The ij gene appears to be a
specific mutator of extranuclear DNA and displays
normal Mendelian inheritance whereas the striping
itself is maternally transmitted. Defects in plastid
RNA polymerase have been implicated in this
1
2
3
4
2-strand Normal Normal Normal Normal
Acentric Normal Normal Dicentric
Acentric Acentric Diecentric Dicentric
3-strand
4-strand
1
2
3
4
1
2
3
4
Figure I62. Double crossing over within paracentric inversions. Only 2-strand double crossing over results in two
complete chromosomes. Pericentric inversion heterozygotes do not yield dicentric strands yet the overall genetic
consequences of double recombination are the same as in pericentric inversion heterozygotes
1030 Invertases
I
variegation. (See Silhavy D, Maliga P 1998 Curr
Genet 33[5]340)
Ion: This is a positively (cation) or negatively (anion)
charged atom or radical. electrolyte
Ion Channels: Refers to pores with special passage
specificity, e.g., a membrane protein when bound to
acetylcholine permits the influx of sodium (sodium
channel); a variety of ion channels exist (mechanical-
ly gated, voltage-gated, ligand-gated, cAMP-gated,
etc.). The ion channels may have two or more
subunits like the staves of a barrel. The pores may be
open or closed and different loops may be associated
with them (see Figs. I63 and I64). The pore loop,
which is a common component of many types of ion
channels, determines which ion can penetrate the
pore. The anion-gated ion channels appear to be
structurally different from most of the cationic
channels inasmuch as they may have different subunit
associations creating double or triple pores. Cistrans
isomerization at a proline opens the pore of a
neurotransmitter-gated ion channel (Lummis SCR
et al 2005 Nature [Lond] 438:248). Thousands of
different odors activate in the nose the trimeric G
protein, G
olf,
which in turn activates adenylate
cyclase and the cAMP-gated cation channels open
and transmit the signal to the brain. Some olfactory
receptors utilize the IP
3
-gated ion channels. Cyclic
guanosine monophosphate (cGMP)-gated channels
mediate visual perception. Light rapidly induces the
formation of guanylate cyclase, generating cGMP
and it is degraded by cGMP phosphodiesterase. The
photoreceptors (rhodopsin pigment) are in the retina
of the eye. Voltage-gated Ca
2 +
ion channels regulate
the influx of calcium through the plasma membrane.
The mechanosensitive ion channels sense forces from
the lipid bilayer without proteins (Kung C 2005
Nature [Lond] 436:647). Mechanical stimuli may
affect Ca
2 +
and other ion channels. The L-type ion
channels of the neurons may be shut off when the
intracellular level of calcium increases beyond a
point. The Ca
2 +
ions then serve as widespread
intracellular messengers and regulate many diverse
cellular functions, particularly the secretion of
neurotransmitters. Their modulation is due to the
subunits of the trimeric G protein. The glutamate
receptors, permeable to Na
+
, K
+
, and Ca
2 +
, are
gated by glutamate in eukaryotes and prokaryotes.
The autosomal dominant human disease, periodic
paralysis, appears to be caused by an amino acid
substitution in the subunit of a sodium channel
transmembrane protein. Mutation in sodium chan-
nel SCN5A may slow down myocardial conduction
and may lead to life-threatening cardial arrhythmias.
Cystic fibrosis is due to a defect in the transmem-
brane conductance regulator protein kinase A and
ATP-regulated chloride ion channel. In pancreatic
cells ATP-dependent K
+
channels are important for
glucose-induced insulin secretion and are targets of
sulfonylureas which is used for oral treatment of non-
insulin-dependent diabetes (NIDDM). Truncation of
the sulfonylurea receptor (SUR) causes persistent
hyperinsulinemic hypoglycemia of infancy and
unregulation of insulin secretion in severe hypogly-
cemia. Nearly 60 human diseases are channelopa-
thies, i.e., diseases due to defects in ion channels. The
human genome contains 340 putative ion channel
genes. Over 400 genes in the human genome are
involved with ion channels. Channels can be inward
or outward rectifying, depending on the predominant
direction of the flow of the ions. The rectification is
not always an intrinsic property of the channel protein
but may be controlled by accessory substances,
spermidine, spermine and other polyamines. Gluco-
corticoid stress hormones may also regulate the K
channels. Ion channels regulate the expression of
many genes. signal transduction, SOC, TRP,
G proteins, neurotransmitters, calmodulin,
rhodopsin, periodic paralysis, cystic fibrosis,
IP
3
, dihydropyridine receptor, ryanodine, di-
abetes, hypoglycemia, sulfonylurea, pyrethrin,
LQT, HERG, Andersen syndrome, Jervell
and Lange-Nielson syndrome, Ward-Romano syn-
drome, myokymia, periodic paralysis, hyper-
kalemic periodic paralysis, hypokalemia,
convulsions, epilepsy, migraine, color blind-
ness, glucocorticoid, Bartter syndrome, ataxia,
myotonia, paramyotonia, hyperthermia, salt-
tolerance, patch clamp; Doyle JL, Stubbs L 1998
Trends Genet 14:92; Apse MP et al 1999 Science
285:1256; Hbner CA, Jentsch TJ 2002 Hum Mol
Genet 11:2435; K
+
channel structure: Jiang X et al
2003 Nature [Lond] 423:33, K
+
ion selectivity: Yu S
et al 2004 Nature [Lond] 431: 830; review of
diseases: Gargus JJ 2003 Am J Hum Genet 72:785;
channelopathy mechanisms channel functions:
Two-pore channel
Figure I63. Two-pore channel
Ion Channels 1031
I
Ashcroft FN 2006 Nature [Lond] 440:440; crystal
structure of voltage-dependent potassium channel:
Long SB et al 2005 Science 209:897, potassium
conductance channel crystal structure: Albright RA
et al 2006 Cell 126:1147; Ye S et al 2006 Cell
126:1161, ion channel disease reviews: Nature
[Lond] 2006, vol. 440:439489; http://www.neuro.
wustl.edu/neuromuscular/mother/chan.html, ligand-
gated ion channels: http://www.ebi.ac.uk/compneur-
srv/LGICdb/LGICdb.php.
Open Closed
Figure I64. Open and closed ion channels
Ion-Exchange Resins: These can be cation or anion
exchangers, their cross linkage determines their use
for the separation of molecules of different sizes.
There is a variety of ion exchange resins; they are
produced by the copolymerization of styrene and
divinylbenzene and various other substances and are
combined to produce phosphocelluloses, diethylami-
noethyl-cellulose (DEAE), carboxymethylcellulose
(CMC), etc. They can be used for the separation and
purification of monovalent ions or polyelectrolytes of
high molecular weight.
Ion Exchangers, Cell Membrane: ion channels
Ion Pumps: These mediate ion transport through
membranes by the use of energy (ATP). They ensure
osmotic balance and convert ATP energy into
electrochemical gradients that are utilized by meta-
bolic pathways. proton pump, ion channels,
uptake selective; Dunbar LA, Caplan MJ 2001 J
Biol Chem 276:29617; Gouaux E, MacKinnon R
2005 Science 310:1461.
Ion Trap Mass Analyzer (IT): This is used in connection
with mass spectrometry. It analyzes trapped and
accumulated ions in high throughput equipment. ITis
fast and sensitive but may not be very accurate.
linear ion trap, mass spectrum, proteomics
Ionic Bond: Refers to a non-covalent attachment
between a positively and a negatively charged atom.
Ionization: This is a process for the separation of
molecules into ions. ion
Ionization Chamber: This equipment measures the
radioactivity of gases by the ionizations generated
through molecular collisions. Electrodes collect the
ions and the current (amplified and registered) is
proportional to the radioactivity. scintillation
counter, Geiger counter, radiation measurement
Ionizing Radiation: Refers to high energy electromag-
netic radiation causing intramolecular alterations (ion
pairs) in organic material, thereby capable of
inducing mutation and cancerous transformation in
living cells. Low energy (<2eV) radiation can also
cause damage to the DNA and guanine residues
absorb more electrons than the other bases, especially
in single-stranded DNA (Ray SG et al 2005 Proc Natl
Acad Sci USA 102:15).
The maximum legal permissible occupational
limits for human exposure during a lifetime should
not exceed 0.5 mSv per year; the legal limit actually
should be 0.2 mSv. 1 Sv (Sievert) = 100 rem (rntgen
equivalent man); 1 rem = 1 rad of 250 kVp X-rays.
radiation effects, radiation measurement, radia-
tion hazard assessment, cosmic radiation, physi-
cal mutagens, Gray units, radiation protection,
electromagnetic radiation
Ionophores: These hydrophobic molecules are involved
in ion transport through cell membranes.
Ionotropic Receptors: These receptors mediate the
control of ion channels after binding the appropriate
ligand. Together with metabotropic receptors they
play an important role in nerve synapses. metabo-
tropic receptor, synapse
IP
3
(inositol 1,4,5-trisphosphate): This is derived from
inositol phospholipid PIP
2
. In response to external
signals it releases Ca
2+
from the endoplasmic
reticulum. IP
3
R2 and IP
3
R3 receptors mediate
exocrine secretion, energy metabolism and animal
growth (Futatsugi A et al 2005 Science 309:2232).
phosphoinositides, InsP, olfactogenetics,
exocrine, Ipk1, Ipk2, BCL
IP
5
, IP
6
: These are IP
3
-derived signaling molecules; IP
6
along with other phosphoinositides and nuclear pore
associated proteins are required for mRNA export
from the nucleus. RNA export, InsP, nuclear
pore, Ipk1, Ipk2, ADAR
IPCR: inverse polymerase chain reaction
IPEX (immune dysregulation, polyendocrinopathy,
enteropathy, X-linked): This is caused by mutation
in the region of human chromosome Xp21-Xq13.3
and encodes the FOXP3 protein involved in the
regulation of transcription or RNA splicing. FKH,
autoimmune disease; Sakaguchi S 2004 Annu Rev
Immunol 22:531.
IPI (integrated protein index): This is an inventory of all
the revealed proteins encoded by a genome. IGI
IpI1: Denotes a yeast mitotic histone kinase
1032 Ion-Exchange Resins
I
Ipk1 (inositol polyphosphate kinase): This converts
inositol-1,3,4,5,6-pentakisphosphate (IP
5
) into hex-
akisphosphate (IP
6
). IP
6
is probably a regulator
mRNA export from the nucleus and it modulates
the function of synaptic vesicles by interacting with
synaptogamin. phosphoinositides, Ipk2, RNA
export, synaptogamins
Ipk2 (inositol polyphosphate kinase): This converts
inositol 1,4,5-trisphosphate (IP
3
) into inositol-
1,4,5,6-tetrakisphosphate (IP
4
) and insositol-
1,3,4,5,6-pentakisphosphate (IP
5
). It is likely that
Ipk2 is the same yeast enzyme that was earlier known
as Arg82, a pleiotropic kinase regulating sporulation,
mating, stress, arginine metabolism and transcription.
IP
4
and IP
5
may be effectors for the processes. Ipk2p
may also stabilize MCM1p that is probably required
for Ipk2 function. phosphoinositides, Ipk1,
MCM
IPMDH (isopropylmalate dehydrogenase): -ispropyl-
malate is a precursor of leucine and it is derived from
-ketoisobutyrate.
Ipomoea (morning glory): This is an ornamental plant
with a relatively short life cycle (4 months); it has
many genetic variations. (See Clegg MT, Durbin ML
2003 Nature Rev Genet 4:206)
Ipsilateral: Denotes affecting only one side. contra-
lateral
IPTG: Isopropyl--D-thiogalactoside is a gratuitous
inducer analog of the Lac operon. -galactosidase;
Lac operon, gratuitous inducer
IQ: human intelligence
I - R: hybrid dysgenesis
Ir: HLA genes were previously known as the immune-
response genes that encode the MHC complex.
HLA
IRA1, IRA2: These are negative regulators of RAS in
yeast, antagonistic to CDC25; they are structurally
related to GAP. RAS, GAP; Mitts MR et al 1991
Mol Cell Biol 11:4591.
IRAK (IL-1 activated serine/threonine kinase): A Pelle-
like interleukin receptor-associated serine/threonine
kinase and adaptor of the MyD88 signaling path-
way. IRAK-4 protein deficiency results in lack of
activation of NF-B and MAPK and suscep-
tibility to infection by pyogenic bacteria. IRAK-4 is
involved in the crosstalk between the innate and
adaptive immune systems (Suzuki N et al 2006
Science 311:1927). NK-B, MAPK, interleu-
kins, pyogenic, MyD88, Pelle, Toll, IL-1;
Jensen LE, Whitehead AS 2001 J Biol Chem
276:29037; Kobayashi K et al 2002 Cell 110:191;
Picard C et al 2003 Science 299:2076.
IRB (institutional review board): The board oversees
professional and research activities involving primar-
ily human objects.
IRE (iron responsive element): This is a 28-nucleotide
5-UTR sequence in the ferritin mRNA, it is
necessary for iron regulation. IRE sequences in the
3UTR of the transferrin receptor mRNA protect the
mRNA from degradation if the iron level is low. Iron
is an essential element for many biological functions
but beyond a certain level it may be very toxic
because it reacts with oxygen to form hydroxyl
radicals and damages the macromolecules. In iron
deficiency the cellular metabolism is reprogrammed
and some mRNAs are destroyed in order to cope with
the deficient Fe level (Puig S et al 2005 Cell 120:99).
The quantitative effect of Ireb-2 iron-regulatory
protein on brain degeneration has been debated
(Galy B et al 2006 Nature Genet38:967). ferritin,
transferrin, aconitase, UTR, ROS, hemo-
chromatosis, anemia; Andrews NC 2000 Annu Rev
Genomics Hum Genet 1:175, dual structure of IRE as
mRNA complex and aconitase: Walden WE et al
Science 2006 314:1903.
Ire: This yeast protein kinase and endoribonuclease is
functionally homologous to mammalian JNK and
SAPK. Ire1 is a transmembrane protein bound in the
cytoplasm to TRAF2, an adaptor protein in signal
transduction. Ire signals the stress in the endoplasmic
reticulum (ER) when the proteins inside are not
folded properly and activation of the chaperones is
needed. ER stress is monitored by PERK. ribonu-
clease L, JNK, SAPK, chaperone, PERK
IRES (internal ribosome entry site, also called RLP):
This may be present in circular viral RNAs
(picornaviruses) and can be translated on eukaryotic
ribosomes. These viral RNAs (300450 nucleotides)
are not capped at the 5-untranslated region and carry
several AUG codons, and show specific sequences
serving as ribosome landing pads. IRES alone can
initiate translation and can replace the 1000-kD
initiation factor complex. The 5S ribosomal protein
interacts with the IRES. By contacting the ribosomes
it changes the structure of both the 40S and 60S0
subunits. The crystal structure of one single viral
IRES has been revealed (Pfingsten JS et al 2006
Science 314:1450). The interaction with ribosomes
requires the cellular eIF-4F eukaryotic translation
initiation factor. Recently, IRES-type elements have
been found in other viruses and in eukaryotes. Many
of the IRES-mediated translation products of eukar-
yotes are involved in important cellular processes
(development, cell cycle, apoptosis). The IRES
IRES 1033
I
containing non-coding regions (5NCR) is generally
longer than the regular 5-UTRs. The presence of
IRES elements (9 or double of 9 nucleotides) permits
the dicistronic transcription of genes and facilitates
gene targeting, homologous recombination and
modification of gene expression. The use of promo-
terless vector constructs positions the IRES carrying
sequences within the transcribed regions rather than
into the non-translated regions of the genome. The
IRES elements are frequently borrowed from
the encephalomyocarditis virus (EMCV) family.
The advantage of this system is that it does not
interfere with the regular Cap-mediated ribosome
scanning. In hepatitis C virus, the IRES mediates the
assembly of the translation initiation complex (Otto
GA, Puglisi JD 2004 Cell 119:369). In dicistronic
vectors, genes placed downstream of the IRES are
transcribed more efficiently than those positioned in
front of it.
The IRES elements can enhance translation and
therefore their identification may help modify gene
expression. The vector outlined here assists in the
identification of the IRES elements (see Fig. I65).
The first cistron reveals their presence by the reporter
and the second cistron binds to the Gal4 upstream
activating sequences and with the aid of VP16 herpes
virus activator facilitates the screening and identifi-
cation of the IRES elements.The Drosophila insulin-
like receptor (dINR) pathway incorporates 4E-BP
resistant cellular internal ribosome entry site (IRES)
containing mRNAs, to functionally couple transcrip-
tional activation with differential translational control
in a cell that is otherwise translationally repressed by
eIF-4E binding protein (4E-BP). Integrated transcrip-
tional and translational response mechanism specifi-
cally dependent on cellular IRES coordinates an
essential physiological signal responsible for moni-
toring nutrient and cell growth conditions (Marr MT
et al 2007 Genes , Dev 21:175). ribosome scanning,
dicistronic transcription, targeting genes, gene
fusion, eIF4F, eIF4G. picornaviruses, transla-
tion initiation, RLP, apoptosis, capping
enzymes, GFP, GAL4, VP16, shunting;
Holcik M et al 2000 Trends Genet 16:469; Pinkstaff
JK et al 2001 Proc Natl Acad Sci USA 98:2770;
Fukushi S et al 2001 J Biol Chem 276:20824; Hellen
CU, Sarnow P 2001 Genes , Dev 15:1593; Zhou W
et al 2003 Proc Natl Acad Sci USA 100:4457;
Hundsdoerfer P et al 2005 Proc Natl Acad Sci USA
102:23421; http://www.iresite.org/.
Iressa (Gefitinib): This is a potential inhibitor of EGFR
and an anti-cancer drug. On the basis of a large-scale
study in 2004 it was concluded that this drug did not
provide any survival benefits for non-small cell lung
cancer and it was subsequently withdrawn from the
market. However, it may be beneficial for certain
genetic constitutions. Humanized anti-hEGFR anti-
body (Cetuximab) and small molecule inhibitors of
EGFR (Erlotinib or HKI-272) can lead to dramatic
regression of lung tumorigenesis (Ji H et al 2006
Cancer Cell 9:485). EGFR
IRF: This is an interferon-regulatory transcription factor,
a homolog of c25 rat factor. c25, p53, interferon
IRF4: LSIRF
IRIS: This is the circular pigmented membrane in front
of the lens of the eye with the pupil in its center. The
retina lines the inner surface of the eyeball (see
Fig. I66). It contains capillary veins and it is
connected to the optical nerve bundle (not shown in
the Fig. I66). The black spot of the retina (not the
actual color) may be impaired in macular degenera-
tion. macular degeneration
Iris
Pupilla
Comea
Retina
Lens
Figure I66. Retina with macula
IRIS: This is the monocot genus of perennial flowers
(see Fig. I67) (2n = 44, Iris germanica).
Promoter
GFP reporter ICS
GAL4 - VP16
DNA construct
Figure I65. Positive feedback vector. It contains two cistrons; the first with an enhanced green fluorescent reporter
and the second is the GA14 enhancer with viral protein V16. In between the two cistrons (ICS) are IRES elements.
(Modified ofer Zhou, W. et al. 2005 Proc. Natl. Acad. Sci. USA 102:6273)
1034 Iressa
I
Figure I67. Iris germanica flower
Iris Pattern: The iris of the eye with potentially 266
distinguishable physical features provides a pattern
suitable for individual identification when a computer
analyzes the image recorded by a video camera (see
Fig. I68). According to some scholars, this procedure
is superior to any other personal identification
method, including fingerprinting and DNA finger-
printing. Retinal scans can also determine identity
to some degree by the pattern of the vasculature; it
has been used in forensics mainly as a post-mortem
test to ascertain the cause of death, such as stran-
gulation, shaking, and some poisonous substances.
fingerprints, fingerprinting of macromolecules;
Daugman J, Downing C 2001 Proc R Soc Lond B
Biol Sci 268:1737.
Figure I68. Iris pattern
IRM (interference-reflection microscopy): This is used
to study the cell membrane and protein associations
(e.g., in immunological synapse). immunological
synapse
IRMA (immunoradiometric assay): This uses radiola-
beled antibody to quantitate a particular antigen. In
the two-site IRMA two antibodies are used that bind
different epitopes. epitope, ELISA, radioim-
munoassay; Frystyk J et al 2001 Growth Horm IGF
Res 11(2):117.
Iron Age: This is a prehistoric period dating to the third
or fourth millennium; it marks the beginning of
recorded history.
IronMetabolism: Several human diseases involve anoma-
lies in iron metabolism. IRE, hemochromatosis,
transferrin, Friedreich ataxia, sideroblastic ane-
mia, aceruloplasminemia, Hallervorden-Spatz
disease, ferritin, porphyria, anemia, Roy CN,
Andrews NC 2001 Hum Mol Genet 10:2181.
Irradiation: radiation
IRS: Refers to the interferon-response factor. interfer-
on
IRS: insulin receptor substrate
IRS-PCR: (interspersed repetitive sequencepolymer-
ase chain reaction): This is used with radiation
hybrids as a rapid test for identifying the nature of the
putative hybrid cells and also the PCR product is
hybridized as a probe to a normal chromosomal
complement and compare it to the previously
established map. The IRS-PCR can also be used to
screen cosmid and artificial chromosome libraries.
radiation hybrid, PCR; Himmelbauer Het al 2000
Nucleic Acids Res 28[2]:e7.
IS: insertion elements
Isadora: This is an 8.3 kb transposable element of
Drosophila, generally present in 8 copies.
Ischemia: This condition is characterized by restriction
of the blood vessels. It may be a major cause of
stroke. For gene therapy, the introduction of anti-
apoptotic genes, interleukin-1 receptor antagonists,
angiogenesis activating vascular endothelial growth
factor, superoxide dismutase, etc. have been consid-
ered. Among the genetic vectors, injecting adenovi-
rus and herpes virus into the brain or into spinal artery
has yielded promising results. stroke, apoptosis,
interleukin, VEGF, adenovirus, herpes, su-
peroxide dismutase, alcohol, cardiac diseases
I-Sce1: This is an unusual restriction endonuclease,
encoded by yeast mitochondrial introns. It recognizes
18 bp sequences, in the mouse genome it cuts only
once per 7 10
10
bp, i.e., less than once in ten times
the size of the total mouse genome. In a modified
form it is useful for studying the consequences of
double-strand breaks and the mechanism of homolo-
gous recombination. restriction endonuclease,
double-strand break, homologous recombination;
Rouet P et al 1994 Proc Natl Acad Sci USA 91:6064.
ISCNT: Refers to the interspecies somatic cell nuclear
transfer technique. nuclear transplantation
ISGF-3: APRF
Isgylation (interferon modulated gene): This plays a
ubiquitin-like role in various cellular processes.
Isgylation 1035
I
ubiquitin, interferon; Malakhova OA et al 2003
Genes, Development 17:455.
ISIS (isotype-specific inhibitory sequence): Various
types of antisense constructs are effective in reducing
or eliminating gene translation. antisense technol-
ogies, isotype
Island Model of Populations: A group of subdivided
populations exchanges m alleles with each other
regularly and also has a chance to receive alleles at a
constant m 1 rate from an earlier population. The
situation resembles that of a drift in a single
population under migration pressure. The model
assumes that each subpopulation has the same size
and is equidistant from each other. The continuous
model version considers equal density at any point
and the discontinuous version assumes that the
subpopulations are clustered at nodal points of a
lattice. Each of these distributions may be one- or
two-dimensional. The discontinuous model is also
known as the stepping-stone model and it may be
three-dimensional. All variations of the basic model
have been criticized because most of the basic
stipulations may not be met under natural conditions.
(See the theoretical details in Cavalli-Sforza LL,
Bodmer WF 1971 The Genetics of Human Popula-
tions, pp 423 ff.)
Isoacceptor tRNAs: This group of different tRNAs
accepts the same amino acid. The identity of a
specific isoaccepting tRNA is determined by particu-
lar nucleotide sites within the group. The anticodon
may serve as an identity site, however the six serine
tRNAs do not share a common anticodon base. The
nucleotide 73 is a discriminator base and the first base
pairs within the acceptor stem. The long variable arm
of the tRNA
Ser
, the extra G1:C73 bp in tRNA
His
, and
the G3:U70 bp in tRNA
Ala
can characterize E. coli
tRNAs. In other species identity may be differently
determined. The anticodon-flanking nucleosides may
play an important discriminating role. tRNA,
aminoacyl-tRNA synthetase, wobble, protein
synthesis, transcript; Heyman T et al 1994 FEBS
Lett 347[23]:143; Chaley MB et al 1999 J Mol Evol
48[2]:168; Crain PF et al 2002 RNA 8:752; Agris P
2004 Nucleic Acids Res. 32:223.
Isoalleles: These are wild type alleles which can be
distinguished only by special techniques. allele,
Harris MJ, Juriloff DM1989 J Hered 80[2]:127; King
JL 1974 Genetics 76:607.
Isoallotype: Refers to variable antigens of one immu-
noglobulin (IgG) molecule subclass which are
invariant on the molecules of another subclass or
subclasses. allotype; Delacroix DL et al 1986 Mol
Immunol 23[4]:367.
Isoantigen: This is an allelic variant of an antigen within
the species. alloantigen
Isobrachial: This means that the two arms of a chromo-
some are identical (see Fig. I69). isochromosome,
chromosome arm, chromosome morphology
Figure I69. Isobrachial chromosome
Isochores: Refers to segments (generally larger than
200 kb) of the DNA of higher eukaryotes having
rather homogeneous GC or AT content. Usually one
light and two or three different heavy components can
be separated by buoyant density centrifugation in the
presence of certain ligands, e.g., silver ions (Ag
+
). In
the mammalian genome the GC- poor isochores
represent about 62% and the GC-rich and GC-very
rich isochores constitute 22% and 34% of the
genome. Genes within isochores have base content
characteristic of isochores. In high GC isochores the
gene concentration is much higher than in the AT-rich
areas. Isochores may affect codon usage and replica-
tion pattern. The cytologically identifiable Giemsa-
stained bands are low in GC, the T bands are high and
the R bands occupy a position in between. Because of
the high GCcontent of the T bands, their codon usage
is biased. R bands and G/R borders are characterized
by a higher frequency of chromosomal exchanges
(breakage and chiasmata). Viral and transposon
integration sites are correlated with the base compo-
sition of the elements; sequences similar to their own
are the preferred targets. The origin of isochores has
been attributed to natural selection or variation in
mutational bias. Recent evidence supports the latter
view. CpG islands, chromosome banding, co-
don usage, transposons; Bernardi G 2000 Gene
241:3; Galtier N et al 2001 Genetics 159:907;
Vinogradov AS 2005 Nucleic Acids Res 33:559.
Isochromatid Breaks: Refers to damage simultaneously
inflicted to both chromatids of a single chromosome
(see Fig. I70). radiation effects
Isochromatid break
Centromere
Figure I70. (Courtesy of B.R. Brinkley)
Isochromosome: This has two identical arms and is
normally produced by a misdivision of a telocentric
1036 ISIS
I
chromosome. misdivision, trisomic secondary,
isobrachial
Isodiametric: Its diameters (lines passing through it
center) are the same in all directions.
Isodisomy: uniparental disomy
Isoelectric Focusing: This is an electrophoretic separa-
tion technique based on the isoelectric point of the
molecules to be separated. The isoelectric point is at a
pH where a solute has no electric charge and thus
does not move in the electric field. For example,
when, denatured protein mixture is placed in an
electrophoretic gel that contains a pH gradient
established by different buffers, the polypeptides
migrate to their isoelectric zones. electrophoresis,
two-dimensional electrophoresis
Isoelectric Point (pI): This is a point when a charged
molecule in a solutionbecause of the pHshows
no net electric potential and consequently does not
move in an electric field. isoelectric focusing
Isoenzymes (isozyme): These are multiple, distinguish-
able forms (by primary structure [electrophoretic
mobility], substrate affinity, reaction velocity and/or
regulation) of enzymes that catalyze the same
reaction. Sorting isozymes are targeted to specific
subcellular compartments, e.g., mitochondria, chlo-
roplast or to different organs (see Fig. I71). isozyme
Heart muscle
(+)
LDH-1
2
3
4
5
Adult 9 5 1 +12 +21
()
Figure I71. Lactatedehydrogenase isoenzyme profile
in the heart muscles in the mouse shows dramatic
changes during development. Nine days before birth,
isozyme LDH-5 is predominant, and LDH-1, LDH-
2 OR LDH-3 are not detectable. In the adult animal
almost the opposite is true. LDHIs a key enzyme in the
pathway of converting sugars into amino acids, lipids,
etc. The numbers at the bottomindicate days before (-)
or after (+) birth. (FromMarkerts CL. ,Ursprung U1971
Developmental Genetics. Prentice-Hall, Englewood
Cliffs, NJ.)
Isofemale: Refers to a line descended from the same
female ancestor which was originally infected by a
cytoplasmically infected bacterium, e.g., in Drosoph-
ila by Wolbachia. Wolbachia
Isoflavones: phytoestrogens
Isoform: Due to differences in amino acid composition,
caused by mutation or alternative splicing of the RNA
transcript, RNA editing, use of alternative promoters
and post-transcriptional or post-translational proces-
sing essentially the same protein is somewhat altered.
Polypeptides in the cellular organelles may basically
have a similar catalytic function as those residing in
the cytosol or organ- or tissue-specific forms of
enzymes. The human WT1 (Wilms tumor) has 24
isoforms and they all share four C-terminal C
2
H
2
Zinc fingers and an N-terminal Pro/Gln-rich regu-
latory domain. alternative splicing, splicing,
Wilms tumor; Hastie ND 2001 Cell 106:391.
Isogamy: Similar gametes are involved in a sexual
union, e.g., in protozoa. anisogamy, heteroga-
metic, homogametic
Isogenic Stocks: Their genes are represented by the
same alleles at all loci. For practical purposes,
isogenicity in rodents is tested by skin grafts. Grafts
within inbred lines are believed to be successful but
not those in between different inbred lines. Grafts
from parents to F
1
are supposed to be successful but
not in the opposite direction. congenic
Isograft: In this the genotype of the donor and recipient
tissues matches. allograft, heterograft, grafting
in medicine
Isoguanine (guanopterin, oxyadenine): This purine
analog can pair with thymidine and can cause
infidelity of PCR (see Fig. I72). Using 2-thiothymi-
dine triphosphate most of the problems can be
prevented because thymidine does not pair well with
this purine analog although it can form three
hydrogen bonds with isoguanine. Isoguanine can
also form three hydrogen bonds with isocytidine. In
expanding the bases to 6 in addition to A, T, G, C
fidelity per round of PCR amplification was about
98%. Such a 6-letter alphabet although not entirely
palatable to DNA polymerases, is a system capable of
Darwinian evolution (Sismour AM, Benner SA 2005
Nucleic Acids Res 33:5640). thiouracil, PCR,
base analogs
N
N
N
N
NH
2
HO
H
Figure I72. Isoguanine
Isoguanine 1037
I
Isolabeling: Refers to
3
H label (or other) in both
daughter chromatids after one replication in
3
H-
thymidine medium (or other labeling medium) at a
certain tract(s) as a consequence of sister chromatid
exchange (see Fig. I73). sister chromatid exchange
Figure I73. Isolabeling
Isolation Genetic: This may be determined by the pre-
sence of inversions in the population that in the case
of recombination yield defective gametes. Also, since
recombination within inverted segments produces
defective gametes, advantageous gene blocks may
be preserved as supergenes. Genetic isolation
may be the first step in speciation. incompatibility
Isoleucine-Valine Biosynthetic Pathway : Steps 1 and
2 are controlled by identical enzymes in both
pathways in several organisms and therefore genetic
defects in either may generate nutritional requirement
for valine [CH
3
CH(CH
3
)CH(NH
2
)COOH] as well as
isoleucine [CH
3
CH(CH
2
CH
3
)CH(NH
2
)COOH] or
the accumulation of the intermediates (see Fig. I74).
The maple syrup urine disease (MSUD) is manifested
in different forms in humans and other mammals and
it is caused by a block in the degradation, the
decarboxylation (step 2) and accumulation of leucine,
isoleucine and valine. The keto-methylvalerate accu-
mulation then causes the characteristic maple syrup
odor of the urine. One of the genes (MSUD II) has
been assigned to human chromosome 1p31 and a
pseudogene to chromosome 3q24. The more serious
aspects of the disease are physical and mental
retardation, potential coma and death. The disease
is also controlled by non-allelic recessive genes,
(BCKDHA [branched chain keto acid decarboxylase
and dehydrogenase] locus is at 19q13.1-q13.2,
BCKDHB is at 6p22-p21). Gene A is responsible
for the biosynthesis of the chain of the enzyme
(BCKDHA) and locus B for the chain (BCKDHB).
In one form of the A type disease the administration
of thiamin (10 mg/day) reduced hyperaminoacidemia
without dietary limitations. The larger subunit (M
r
46,500) of the enzyme is part of a mitochondrial
protein complex. The enzyme complex also contains
component E2 (M
r
52,000) that transfers the acyl
group of the keto acid from the E1 component
(protein A) to coenzyme A. The disease may be due
to a single base pair change resulting in a tyrosine
substitution at asparagine site 394 of protein A or to
deletions of several nucleotides. The defect is
detectable prenatally but carriers cannot be identified
because of recessivity. The prevalence varies greatly
from 3 10
5
to 6 10
3
in different ethnic groups.
Defects in the transaminase reaction (step 3) may also
be controlled by a common glutamic-branched-
chain-amino acid transaminase. In humans, however,
hypervalinemia (valinemia) is caused by a defect in a
specific transaminase, resulting in the lack of ability
to catabolize valine into keto-isovalerate without
affecting the level of leucine and isoleucine in the
blood.
MSUD III (7q31-q32) is caused by dihydrolipoa-
mide dehydrogenase deficiency. Methyl-crotonyl-
CoA carboxylase deficiency (3q25-q27) is a recessive
defect in leucine catabolism without acidosis. Spinal
defects result in muscular hypotony and atrophy.
Isovaleric acid CoA dehydrogenase deficiency
(15q14-q15) is a ketoacidosis with isovaleric acade-
mia and is similar to MSUD; the clinical symptoms
include retarded psychomotor activity, vomiting and
protein aversion. In the Mediterranean (North Africa)
region, the disease is known as Fenugreek Tea disease
because the odor of the urine is reminiscent of the
extract of Trigonella foenum graecum L. A nitrosour-
ea-induced mutation in mice blocks the mitochondrial
pathway of branched-chain amino acids and can be
used as an animal model (Wu J-Y et al 2004 J
Clin Invest 113:434). genetic screening, hyper-
valinemia, 3-hydroxy-3-methyl-glutaryl CoA lyase
deficiency, leucine metabolism, methylcro-
tonylglycinemia, methylglutaconicaciduria, hy-
droxymethylglutaricaciduria, methacrylaciduria,
methylacetoaceticaciduria, 2-methyl-3-hydroxy-
butyryl-CoA dehydrogenase deficiency; Nellis MM,
Danner DJ 2001 Am J Hum Genet 68:232.
Isolocus: Refers to paralogous locus that originates
from duplication of the genome. paralogous loci
Isomerase: This is an enzyme that interconverts
enantiomorphs. enantiomorph, chirality
Isomerism: This is a developmental anomaly displaying
single organs, present normally asymmetrically in the
body, in a position symmetrical on the two sides of
ketohydroxy-methylvalerate
ketohydroxy-isovalerate
dihydroxy-methylvalerate
1 2 3
dihydroxy-isovalerate keto-isovalerate
keto-methylvalerate isoleucine
valine
Figure I74. Isoleucinevaline biosynthetic pathway
1038 Isolabeling
I
the body axis. heterotaxy, situs inversus viscer-
um, left-right asymmetry
Isomerization of Strands: One crossed over DNAstrand
changes into a two-strand crossover through the
rotation of molecules. Isomerization occurs in a
triplex formation, such as when RNA is transcribed
on the DNA template (Cannon WVet al 2000 Nature
Struct Biol 7:594). Meselson-Radding model of
recombination, Hoogsteen pairing
Isomers: These are different compounds that have the
same molecular formula but their structure varies.
Their differences may be relatively subtle (D- and L-
glucose) or may be as large as that between ethyl
alcohol and methyl ether.
Isometric Phage: This is enclosed in an icosahedral or
similar multifaceted globe-shape capsid. Many ico-
sahedral viruses contain a protruding structure
outside the icosahedral that serves as a packaging
and injection portal (see Fig. I75). (Jiang Wet al 2006
Nature [Lond] 439:612).
Figure I75. Icosahedron
Isonymy: There is a probability of kinship between
individuals with the same family name. According to
some scholars, the frequency of isonymous couples
multiplied by a factor of 1/4 may provide information
on the coefficient of inbreeding in the population.
One-fourth of the married pairs have identical family
names before marriage because of the inheritance of
the grandfathers name through two sibs and the
remaining three-quarters have different surnames.
The probability of isonymy is 1/4 for first cousins,
1/16 for second cousins and 1/64 for third cousins.
When multiplied by 1/4 these fractions provide the
coefficient of inbreeding, i.e., (1/4 1/4) = 1/16,
(1/16 1/4) = 1/64, and 1/64 1/4) = 1/256 for
the three types of matings, respectively. One study
found that 24% of Englishmen sharing the same
family name also shared the Ychromosome (King TE
et al 2006 Current Biol 16:384). (See Lasker GW,
Mascie-Taylor CG 2001 Ann Hum Biol 28:546)
Isopentenyladenine (6-[,-dimethylallylamino]purine):
A post-transcriptionally modified base in tRNA; it is
also a cytokinin plant hormone. tRNA, plant
hormones; Takei K et al 2001 J Biol Chem
276:26405.
Isopeptidases: These are de-ubiqitinating enzymes.
ubiquitin, UBP
Isoprene: 2-methyl-1,3 butadiene unit of terpenoids,
fragrances, rubber, etc. Isoprenylated proteins are
anchored to the cell membranes (see Fig. I76). The
role of the oncogene product, RAS, functions in
carcinogenesis and signal transduction in isopreny-
lated form, attached to a farnesyl pyrophosphate.
RAS, signal transduction, membrane proteins,
prenylation, plastoquinone; Lichtenthaler HK
1999 Annu Rev Plant Physiol Plant Mol Biol 50:47.
CH
3
CH
2
= C - CH = CH
2
Figure I76. Isoprene
Isoprenoids: These include > 23,000 diverse com-
pounds in viruses to mammals such as cholesterol,
steroid hormones, bile acids, retinoids, isopentenyl-
tRNA, sphingomyelins, ecdysone, gib-berellic acid,
abscisic acid, brassinosteroids, carotenoids, rubber,
etc. They may function as regulators of transcription,
developmental processes involving the hedgehog
family of proteins, meiosis, apoptosis, etc. (See
Niemann-Pick disease, SF-1, hedgehog, apoptosis,
Edwards PA, Ericsson J 1999 Annu Rev Biochem
68:157; Sharkey TD, Yeh S 2001 Annu Rev Plant
Physiol Plant Mol Biol 52:407)
Isopropyl Thiogalactoside: IPTG
Isopycnic: These are molecules with equal density.
buoyant density
Isopycnotic Chromosome: This does not display the
heterochromatic regions. heterochromatin
Isoschizomers: These restriction endonucleases have
very similar recognition sites; their cleaved ends
being identical (cohesive) they are capable of joining
each other, e.g.,
Bgl II 5 ApGpApTpCpT
3 TpCpTpApGpA
Bam HI 5 GpGpApTpCpC
3 CpCpTpApGpG
Their termini after ligation are:
GGATCT
CCTAGA
However, this juncture is no longer recognized by
either of the two enzymes because the bases at the left
and right ends are incompatible with both Bgl II or
Bam HI.
Isoschizomers 1039
I
Other isoschizomers are Hpa II 5 CGG 3 does
not cut when is methylated
Msp I 5 CCGG 3 is indifferent to methylation
Isoschizomers SmaI (CCCGGG) and Xma I
(CCCGGG) recognize the same sequence but cut
it () at different position. restriction enzymes,
restriction-modification
Isosteres: These have a similar electron arrangement
but different chemical structures and are used for
substrate analog designs.
Isothermal: Denotes being at identical temperature.
Isotonic: The active salt concentration of this mediumis
the same as in the cell. A NaCl sol-ution of 0.9% is
isotonic with the human blood and can be used to
maintain temporarily good osmotic conditions after
substantial bleeding by injecting sterile sol. natr.-
chlor. isotonica into the (blood vessels) venae.
hypotonic, isotonic
Isotope Discrimination: The heavier atoms may be used
less effectively than the lighter ones. isotopes
Isotope-Coded Affinity Tags (ICAT): Two chemicals
with biotin affinity and a thiol group are labeled with
a heavy or light isotope, respectively. The experi-
mental and the control proteins are reduced and
derivatized with either the heavy or the light forms.
The mixed samples are digested to obtain peptide
fingerprints. The tagged fragments are analyzed by
mass spectrometry after purification. Only the double
peaks with 8 Da difference (i.e., the difference
between the light and heavy labels) are further
characterized (Gygi SP et al 1999 Nature Biotechnol
17:994). Non-isotopic labeling techniques have also
been developed. mass spectrometer [MALDI/TOF/
MS], non-isotopic labeling, proteomics
Isotopes: Two or more nuclides having the same atomic
number are the same elements but differ either in
mass (stable isotopes, such as Hydrogen and
Deuterium) or radioactive isotopes (atom) that
disintegrate by emission of corpuscular or electro-
magnetic radiation (, rays). The latter ones are
particularly useful in biology as radioactive tracers
of minute amounts of labeled (H
3
, C
14
, P
32
)
nucleotides or (C
14
, S
35
,I
125
) proteins. Stable isotopes
(N
15
, C
13
, H
2
) can also be used as density labels for
distinguishing old and newly synthesized molecules.
The types of radiations and energies in million
electron volts are H
3
: , 0.0170.019, C
14
: 0.155,
P
32
: 1.71, S
35
: 0.167, I
131
: 0.605, 0.250, and
0.164, 0.177, 0.284, 0.364, 0.625, I
125
: 0.0355, Y
90
:
2.24, K
42
: 3.6, 2.4 and 1.5, Cs
137
: 0.518, 1.17
and 0.663, Co
60
: 1.56, 2.33, U
238
: 4.180,
0.045, Ra
226
is generally understood to be radium; it
has a long half-life (1,620 years) and is quite stable.
It primarily emits radiation (helium nuclei) 4.750
MeV and electromagnetic radiation (0.188 MeV).
Radium is converted into a number of other isotopes.
Among these radon, the commonly present gas
diffusing from rocky soils, has a short half-life
(3.825 days) yet it is usually replenished from the
source. It emits radiation and may pose an
environmental health hazard if its concentration
levels increase. Radium is no longer used for medical
or to a very limited extent for industrial purposes
because of the hazards involved in handling.
Luminous watch dials are made now from fluor-
ochromes. Curie, C, fluorochromes, biotin,
non-isotopic labeling, half-life, radiocarbon
dating, argon dating
Isotopic Graft: A group of cells or a piece of tissue is
transplanted to the equivalent position of another
animal.
Isotype: Refers to closely similar immunoglobulins
with differences in the constant region. Sometimes
the word is used in a broader sense to imply similar in
constitution or sequence. immunoglobulins, allo-
type, idiotype
Isotype Switching: Refers to a process of immunoglob-
ulin gene rearrangement. immunoglobulins
Isotypic Exclusion: Either only or light chains are
used with any of the heavy chains for the formation
of a particular antibody (both light chains cannot be
used simultaneously). antibody, immunoglobulins
Isovaleric Acidemia (IVD): This disorder is controlled
by a recessive gene in human chromosome 15q14-
q15. It is characterized by sweaty feet-like odor
(butyric and hexanoic acid) of the urine, dislike of
protein, vomiting, anemia, ketoacidosis, high iso-
valeric acid content of the blood leading to injury of
the nervous system. The biochemical lesion is in
isovaleric acid CoA dehydrogenase deficiency.
Several types of mRNAs of this gene have been
identified on the basis of differences in transcription
and different mutations or deletions. amino acid
metabolism, isoleucine-valine biosynthetic path-
way, Jamaican vomiting sickness, acetyl-CoA
dehydrogenase deficiency
Isozyme: (see Fig. I77) isoenzymes
Figure I77. Fructose-1,6-diphosphate aldolase iso-
zymes
1040 Isosteres
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Isozygotic: This means homozygous for all genes.
ISP45: mitochondrial import
ISPCR: Denotes in situ polymerase chain reaction.
in situ PCR
ISRE (interferon sequence response element): signal
transduction [Jak-STAT]
ISSR (inter-simple sequence repeats): Refers to repeats
between non-repeated sequences of chromosomes.
IST: Denotes interaction sequence tag.
ISTR (inverse sequence-tagged repeat): This technique
is used for physical mapping of genomes. (See Rohde
W J 1996 J Genet Breed 50:249)
ISWI: This is the ATPase subunit of NURF and other
chromatin remodeling proteins. nucleosome, nu-
clear receptors, chromatin remodeling; Nurf,
Langst G, Becker PB 2001 J Cell Sci 114:2561;
Xiao H et al 2001 Mol Cell 8:531; Clapier CR et al
2002 Nucleic Acids Res 30:649.
ITAM (immune receptor tyrosine-based activation
motif): lymphocytes, ZAP-70, T cell receptor,
BLK, ITIM, killer cell, osteoclast, (see
Fig. I78).
Antigen
IgM antibody
Cell membrane
Ig
Ig
Disulfide
Ig
Ig
Figure I78. ITAMs are phosphorylated by Lck, Blk,
Flyn, Lyn and recognized by Syk. Phosphorylation and
activation may be initiated by cross-linking antigen of
IgM molecules
ITCH: This is E3 type ligase, its activity is promoted by
phosphorylation. It plays an important role in the
differentiation of lymphocytes (Gallagher Eet al 2006
Proc Natl Acad Sci USA 103:1717). ubiquitin
ITD: idiopathic torsion dystonia
Iteration: This refers to repetitions; a commonly
used form is the iterated integral when an individ-
ual differentiates first with respect to one of the
variables while holding the other constant and then
differentiates the result with respect to the other
variable. For biological experiments the distribution
may be fitted to a negative binomial, requiring a
similar procedure in the calculation of the maximum
likelihood of values. For complex numerical itera-
tions computer programs may be required. negative
binomial, maximum likelihood
Iterative Crosses: These are used in breeding programs
such as three-way and double-crosses employed for
the testing or production of hybrid maize. heterosis
Iterative Truncation (ITCHY, incremental truncation for
the creation of hybrid enzymes): This method is used
to generate hybrid enzymes by fusing truncated N- or
C-terminal fragment libraries . The technique of crea-
tion enhanced cross over between non-homologous
proteins has been termed SCRATCHY (Kawarasaki
Y et al 2003 Nucleic Acids Res 31(21):e126). The
DNA coding sequences are progressively reduced
with the assistance of exonuclease III before ligating
the single-crossover hybrid library. The newcoding
sequence may be the same length as theparental
ones except that parental contribution to the hybrid
may vary. The components of the newly created
protein may be as different as prokaryotic and
eukaryotic. protein engineering, DNA shuffling;
Ostermeier M et al 1999 Proc Natl Acad Sci USA
96:3562; Lutz S et al 2001 Proc Natl Acad Sci
USA 98:11248; Griswold KE et al 2005 Proc Natl
Acad Sci USA 102:10082., see Fig. I79)
PARENTAL
HYBRID
Figure I79. Iterative truncation
Iterons: These multiple, short DNA repeats may bind to
the plasmid replication protein and may either initiate
or inhibit replication. (See Chattoraj DK 2000 Mol
Microbiol 37[3]:467)
Iteroparity: Reproduction takes place on more than a
single occasion.
ITG: integrin
ITIM(immunoreceptor tyrosine-based inhibitory motif):
Typically, the cytoplasmic domain of these molecules
contains six amino acids Ile/Val/Leu/Ser)-X-Tyr-X-
X-(Leu, Val) where X can be any amino acid. A
ITIM 1041
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balance between activation (ITAM) and inhibition
motifs determines the development of the immune
system (NK). Clustering of these receptor sites is
induced by ligands and a Src type kinase phosphor-
ylates the tyrosine residue. Such an event facilitates
the recruitment of SH2 domain phosphatases such as
SHP-1 and SHIP. PIR-B attenuates B cell receptor
activation in cooperation with SHP-1. Other targets
are Sky, BLNK, BASH, phosholipase C, FcR, etc.
killer cells, ITAM, SH2, SHP-1, SHIP,
PIR, Sky, BLNK, B lymphocyte receptor,
BASH, phospholipases, FcR, KIR, DAP;
Ravetch JV, Lanier LL 2000 Science 290:84.
ITK: This is a non-receptor tyrosine kinase of the Tec
family; it signals to TCR. TCR, Tec
ITP: Denotes inosine triphosphate. hypoxanthine,
inosine
ITR: Refers to inverted terminal repetition such as
observed in human adenovirus DNA. adenovirus
ITS: Internal transcribed spacers are short sequences
within eukaryotic pre-tRNA transcription units (5
18S - ITS - 5.8S - ITS - 28S 3), and these clusters are
separated by external tran-scribed spacers. Their
analysis facilitates identification of different strains.
ETS, tRNA; Fujita SI et al 2001 J Clin Micro-
biol 39:3617; ITS2 database: http://darwin.uvigo.es/
software/modeltest_server.html.
IU: IU
IUCD (intrauterine contraceptive device): This method
prevents implantation of the egg. Although it is an
effective method of birth control, it may lead to
infection and may cause some discomfort.
IUGT (in utero gene transfer): Used to correct genetic
defects of somatic cells by transfer of gene(s) into the
unborn fetus. Its advantage is that it can be applied
early during embryonic development before irrevers-
ible damage occurs, e.g., in various neurological
diseases (Tay-Sachs, Niemann-Pick, Lesh-Nyhan,
Sandhoff, Leigh, leukodystrophies, gangliosidoses,
immunological disorders, thalassemias, osteopetro-
sis). It is less likely that IUGT involves vector or cell
rejection. The treatment of hematopoietic stem cells
may be more successful. Animal experiments have
yielded encouraging results. Its drawbacks are the
potential risk to the mother and the fetus. Also, the
vector DNA may cause undesirable insertions or
mutations in the germline. ART, gene therapy,
Heikkila A et al 2001 Gene Ther 8:784.
IUI: intrauterine fertilization, ART
Ivemark Syndrome: asplenia
Ivermectin: An antibiotic used to treat parasitic
infections.
IVET (in vivo expression technology): This technology
selects specifically induced bacterial genes that are
expressed when bacteria are committed to infection
or passage through a host.
IVIG (intravenous immunoglobulin gamma): Its admin-
istration provides polyclonal anti-inflammatory ef-
fectiveness against autoimmune cytopenias, Guillain-
Barr syndrome, myasthenia gravis, anti-Factor VIII
autoimmune disease, dermatomyositis, vasculitis
(inflammation of the blood vessels) and uveitis (eye
inflammation). cytopenia, Guillain-Barr syn-
drome, myasthenia, anti hemophilic factors,
polyomyositis
IVF: in vitro fertilization, ART
IVS: Refers to intervening sequences, they are the same
as introns. introns
Ixodoidea (ticks): Group of insects, that are common
carriers of Borrelia infection, causing Lyme disease
and viral infections resulting in encephalitis (see Fig.
I80). The insects saliva contains anticoagulant
proteins (e.g., Salp 14) that facilitate their feeding
on the host and transmission of the tick-borne
pathogens. Borrelia, Narasimhan S et al 2004 Proc
Natl Acad Sci USA 101:1141.
Figure I80. Tick
Izumo: An immunoglobulin-like sperm protein that
mediates sperm fusion with the oocytes.
1042 ITK
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Historical vignettes
Professor TH Morgan in The American Naturalist
60, p. 490 (1926)
except for the rare cases of plastid inheritance,
the inheritance of all known characters can be
sufficiently accounted for by the presence of genes
in the chromosomes. In a word the cytoplasm may
be ignored genetically.
In his AHistory of Genetics (Harper &Row, New
York, 1965) AH Sturtevant comments on the
significance of Walter S. Suttons papers (Biol.
Bull. 4:24 [1902] and ibid. 231 [1903]) on the
correlation between chromosomal segregation and
the Mendelian laws:
With this paper, this phase of the history is
finished. The conclusions were not at once general-
ly accepted, but they could not be disregarded and
stand today as essentially correct. At last, cytology
and genetics were brought into intimate relation,
and results in each field began to have strong effects
on the other.
(It may be worth noting that Sutton, a student of
the great EB Wilson, never completed his graduate
studies at Columbia University and without a Ph.D.
he went on to become a MD and a distinguished
practicing surgeon. He also had special engineering
talents but quit cytology and genetics where he
made such a lasting impact. Sutton died at the age
of 39. [See Crow EW & Crow JF 2002 Genetics
160:1])
Izumo 1043
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