Genetics

Dr.Arzeena
 Genetic Information
• Gene – basic unit of genetic
information. Genes
determine the inherited
characters.

• Genome – the collection of

genetic information.

• Chromosomes – storage
units of genes.

• DNA - is a nucleic acid that

contains the genetic
instructions specifying the
biological development of all
cellular forms of life 2
 Chromosome Logical Structure
• Locus – location of a gene/marker
on the chromosome.

• Allele – one variant form of a

gene/marker at a particular locus.

Locus1
Possible Alleles: A1,A2

Locus2
Possible Alleles: B1,B2,B3

3
 Human Genome
Most human cells
contain 46 chromosomes:

• 2 sex chromosomes (X,Y):

XY – in males.
XX – in females.

• 22 pairs of chromosomes
named autosomes.

4
Genotypes Phenotypes

• At each locus (except for sex chromosomes)

there are 2 genes. These constitute the
individual’s genotype at the locus.

• The expression of a genotype is termed a

phenotype. For example, hair color, weight,
or the presence or absence of a disease.

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 General considerations
• Human genome is complete.
• Less then 2% genes code for proteins.
• By alternative splicing 25,000 human genes
can code for 100,000 proteins.
• Humans share 99.5% of their DNA.
• Variability in only 0.5% of their sequences.
 DNA variations
• SNP’s- single nucleotide polymorphisms, at
isolated nucleotide positions, usually biallelic.

• CNV’s- copy number variations, different

number of large contiguous stretches of DNA
from 1000 to millions of base pairs.
• A very large number of genes do not encode
proteins they have regulatory functions

• Recently discovered small RNA molecules play

an important role.

• Silencing of genes preserved in all living forms,

from plants to animals.

• Discovered by Andrew Fire and Craig Mello for

which they received a Nobel prize in 2006.
 Mutations
1.Point mutations within coding sequences-
• Conservative missense
• Non conservative missense
• Non sense /stop codon.
2.Mutations within noncoding sequences -
• Mutations involving the promoter and
enhancer sequences may affect the binding of
transcription factors
• They may also lead to defective splicing of
intervening sequences.
• Marked reduction or total lack of transcription
,thus failure to form mature m-RNA and
further translation.

• Eg: - few forms of hereditary anemias

3.Deletions and insertions - lead to alterations
in the reading frame of the DNA strand.
4. Trinucleotide repeat mutations-
• characterized by amplification of a
trinucleotide sequence.
• Eg: fragile X syndrome
• 250-4000 repeats of the sequence CGG in the
FMR1 gene.
• dynamic
 Human genetic disorders
Broadly classified into

• Disorders related to mutations in single genes.

• Chromosomal disorders.

• Complex multigenic disorders.

• Also added single gene disorders with non-classical

pattern of inheritance
 Dominant vs. Recessive

A dominant allele is
expressed even if it is
paired with a recessive
allele.

A recessive allele is only

visible when paired with
another recessive allele.

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 Mendel’s 1 Law st

Two
Twomembers
membersofofaagene
genepair
pairsegregate
segregatefrom
fromeach
eachother
otherinto
into
the
thegametes,
gametes,so
sohalf
halfthe
thegametes
gametescarry
carryone
onemember
memberof ofthe
the
pair
pairand
andthe
theother
otherhalf
halfcarry
carrythe
theother
othermember
memberof ofthe
thepair.
pair.

Y/y y/y Gamete

production

Gamete
all y
production y/y ½
y½

Y/y ½
Y½
16
 Mendel’s 2 nd
Law
• Different gene pairs assort independently
in gamete formation.

.This “law” is true only in some cases

Gene
Gene pairs
pairs on
on SEPARATE
SEPARATE CHROMOSOMES
CHROMOSOMES
assort
assort independently
independently at
at meiosis.
meiosis.

17
X-linked Inheritance
Different results obtained
from reciprocal crosses
between red-eyed and
white-eyed Drosophila.

Explanation: The gene

responsible for eye-color
is X-linked. Females have
X-chromosomes, while 2
males have 1 X-
chromosome
.and 1 Y-chromosome
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 Single gene disorders/ Mendelian
disorders
When studying these disorders, 5 general
patterns of inheritance are observed:

• Autosomal recessive
• Autosomal dominant
• X-linked recessive
• X-linked dominant

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 Autosomal dominant
• Atleast one parent of an
index case is affected.

• Affects both males and

females.

• When an affected person

marries an unaffected one
every child has a one in two
chance of having the disease.

• e.g., Huntington disease.

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• Some patients do not have affected
parents.

• They owe their disorder to mutations in

either the sperm or ovum.

• Siblings not affected .

• Clinical features can be modified by

variations in penetrance & expressivity
 Autosomal recessive
• Autosomal recessive
traits make up the
largest category of
mendelian disorders.

• The disorder results

when both alleles at a
given locus are mutated.

• Parents unaffected,
siblings may show the
disease. 22
• Siblings also have one in four chance of
having the trait.
• Consanguinity plays an important role.
• Expression more uniform, & onset early.
• Complete penetrance common.
• New mutations rarely occur and take a
long time to be expressed.

• Eg- cystic fibrosis

• All sex linked disorders are X-linked.

• Almost all are recessive.

• Most Genes are located in the male specific

region of Y.

• Any mutation affecting the Y-linked genes

makes the male infertile.
 X-linked recessive
• Many more males than
females show the
disorder.
• Mutant genes on the X
chromosome do not have
corresponding alleles on
the Y chromosome.
• Thus males are said to
be hemizygous for X-
linked mutant genes.

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• All the daughters of an affected male
are “carriers”.

• None of the sons of an affected male

show the disorder or are carriers.

• e.g., hemophilia
 Female carriers-
• Sons have one in two
chance of receiving the
mutant gene.
• Heterozygous female does
not express phenotype
because of the paired
normal allele.
• Partial expression possible
if unfavourable lyonization
occurs.
 X-linked dominant
• Affected males pass the
disorder to all daughters
but to none of their sons,
if the female partner is
unaffected.

• E.g. Vitamin D resistant

rickets.

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• Affected
heterozygous
females married to
unaffected males
pass the condition to
half their sons and
daughters

• e.g. fragile X syndrome

 Biochemical and molecular basis of single
gene disorders
1. Enzyme defects & their consequences.

2. Defects in membrane receptors & transport

systems.

3. Alterations in the structure, functions or quantity

of nonenzyme proteins.

4. Mutations resulting in unusual reactions to drugs.

 ENZYME DEFECTS

eenzy
 Disorders associated with defects in
enzymes

 LYSOSOMAL STORAGE DISEASES.

 GLYCOGEN STORAGE DISEASES

(GLYCOGENOSES).

 ALKAPTONURIA (OCHRONOSIS).
 LYSOSOMAL STORAGE DISEASES
• Lysosomes- key components of intracellular
digestive system.

These enzymes-
• function in acidic environment
• constitute secretory proteins destined only for
intracellular organelles.
Result from lack of any protein that is essential
for normal functioning.
• Lack of enzyme activator.
• Lack of substrate activator.
• Lack of transport protein.

Organ affected depends on

• Tissue where material to be degraded is
found.
• Location where degradation normally occurs
• G m2 gangliosidosis - group of three disorders
included.
1) Hexosaminidase alpha subunit deficiency
(Tay-Sachs).
2) Hexosaminidase beta subunit deficiency
(Sandhoffs).
3) G m2 Gangliosidosis variant AB-ganglioside
activator protein deficiency.
 Tay-Sachs disease
• Mutations in alpha subunit locus on
chromosome 15.
• Prevalent in ashkenazi jews.
• Affected infants normal at birth show signs at
6 months.
• Progressive mental & motor deterioration
leading to muscular flaccidity,
blindness,increasing dementia.
Morphology-
• G m2 ganglioside deposits in
heart ,liver ,spleen.
• Neurons of CNS, ANS, & retina.
• Stains for fat are positive
• whorled configurations- onion skin layers of
membranes in lysosomes.
• Cherry –red spot in macula.
• Chaperone therapy.
 Nieman-Pick disease
• Type A,B,C.
• Inherited deficiency of sphingomyelinase.
• Chromosome 11p15.4
• c/f present at birth & invariably become
evident by 6 months.
• Protuberant abdomen, failure to thrive.
• Progressive deterioration of psychomotor
function.
• Type A- severe infantile form with extensive
neurological involvement.
• Missense mutation causes complete absence
of sphingomyelinase.
• Accumulation in lysosomes,enlarged cells,
zebra bodies on EM.
• Massive spleenomegaly, mild hepatomegaly,
moderate lypmphadenopathy.
• Brain-shrunken gyri ,sunken sulci,diffuse
neuronal involvement.
• Type B – organomegaly ,no CNS involvement.
• Usually survive into adulthood.

• Type C – more common.

• Mutation in NPC1 &2,defective lipid transport.
• Clinically heterogenous.
• Most common form presents as ataxia,
vertical supranuclear gaze palsy, dystonia
dysarthria, psychomotor regression.
 Gauchers disease
• Autosomal recessive disorders,mutations in
the gene encoding glucocerebrosidase.
• Accumulation in CNS, macrophages(gaucher
cells).
• Type 1 & 2.intermediate type 3.
• Type 1- non neuronal,splenic & skeletal.
• Type 2 – acute infantile cerebral pattern
• Gaucher cells found in liver, spleen,bone marrow,
lymph nodes, tonsils, thymus, peyer’s patches.
• Bone marrow involvement may produce areas of
bone erosion-pathologic fractures..
• No storage of lipids in neurons,yet shrivelled and
destroyed progressively.
• c/f in adult life,pancytopenia, thrombocytopenia.
• Type 2 & 3 CNS dysfunction,convulsions dominate.
• More than 150 mutations .
• Replacement & substrate reduction therapy.
 Mucopolysaccharidoses
• MPS I to VII.
• All are autosomal recessive traits,Hunter
syndrome-X linked recessive.
• Alpha-1-iduronidase enzyme deficiency.
• c/f – coarse facial features, clouding of the
cornea, joint stiffness, mental retardation,
balloon cells.
• Hurler syndrome- MPS 1-H, severe form
 Glycogenoses
• Deficiency of various enzymes in glucose
metabolism.
• Based on the pathophysiology divide into
three main subgroups:
• Hepatic-eg. Von Gierke disease.
• Myopathic- eg. McArdle syndrome.
• Miscellaneous- Pompe disease.
 Alkaptonuria (ochronosis)
• Autosomal recessive disorder.
• Lack of homogentisic oxidase in tyrosine
degradation.
• c/f- blue black pigmentation of cartilage,
tendons, connective tissue .
• Degenerative arthropathy
Defects in receptor proteins
 Familial hypercholesterolemia
• Receptor disease.
• Mutation of gene encoding receptor for LDL.
• More than 900 mutations identified.
• Grouped into five classes.
• c/f- tendinous xanthomas, premature
atherosclerosis, increased risk of MI.
• Statins- HMG CoA reductase inhibitors.
DEFECTS IN STRUCTURAL PROTEINS
 Marfan syndrome
• Autosomal dominant inheritance.
• Disorder of connective tissues, manifested by
changes in skeleton, eyes, CVS.
• Defect in fibrillin encoded by FBN1 & 2, on
chromosome 15q12.1,5q23.31.
• Skeletal abnormalities-tall,long extremities, lax
joints hyperextendable thumb, dolichocephaly,
spinal deformities, classical chest deformity(pectus
excavatum).
• Occular changes- subluxation or dislocation of
lens (ectopia lentis) .

• CVS lesions- mitral valve prolapse, dialatation

of ascending aorta, soft billowy valves
leading to regurgitation
 Ehlers-Danlos syndrome
• Defects in fibrillar collagen synthesis.
• Patterns of inheritance varied.
• Skin ,ligaments, joints involved.
• Hypermobile joints, hyperextensible skin
fragile and vulnerable to trauma.
Basic defect in connective tissue may lead to
rupture of colon & large arteries ,ocular
fragility, corneal rupture, retinal detachment.
 CHROMOSOMAL DISORDERS

• STRUCTURAL ABNORMALITIES
• CYTOGENETIC DISORDERS INVOLVING AUTOSOMES
• CYTOGENETIC DISORDERS INVOLVING SEX
CHROMOSOMES
STRUCTURAL ABNORMALITIES
 DISORDERS INVOLVING AUTOSOMES
• DOWNS SYNDROME-trisomy 21

• EDWARDS SYNDROME – trisomy 18

• PATAU SYNDROME – trisomy 13

Downs syndrome
 Edwards
syndrome
 Patau
syndrome
 Disorders involving sex chromosomes
• Klinefelter syndrome

• Turner syndrome
 Klinefelter syndrome
• Male hypogonadism that occurs when there
are 2 or more X chromosomes & one or more
Y chromosomes.
• 1 in 660 live births.
• Diagnosed after puberty.
• Eunuchoid body habitus,long legs, small
atrophic testis,small penis lack of secondary
sexual characteristics,gynaecomastia.
• Lower than normal IQ.
• FSH high ,low testosterone, estrogen
elevated.classic pattern is 47 XXY.
• Testicular atrophy-atrophic hyalinised tubules.
• Higher risk of breast cancer,extra-gonadal
germ cell tumors, AI disorders.
 Turner syndrome
• Complete or partial monosomy of the X
chromosome,characterised by hypogonadism
in phenotypic females.
• 1 in 2000 live births.
• Hermaphroditism and
pseudohermaphroditism
• Genetic sex is determined by the presence or
absence of a Y chromosome.
• Gonadal ,ductal, phenotypic sex ambiguity.
 Triplet repeat mutations
• Long repeating sequences of three nucleotides.
• 1 in 1550 for affected males & 1 in 8000 for
affected females.
• Mutation in the FMR-1 gene.
• Males- long face large everted ears,large
mandible, large testicles.
• Mental retardation because of the loss of FMR
protein.
• Carrier males
• Affected females
• Risk of phenotypic effects- sherman paradox.
• Anticipation
 Mutations in mitochondrial genes
• Leber hereditary optic neuropathy.
• neurodegenerative disease with pogressive
loss of central vision .
• Human mtDNA -37 genes,24 for translation of
mt ,13 for respiratory enzymes.
• Maternal inheritance.
 Genomic imprinting
• Prader willi syndrome.
• Angelman syndrome.
• Chromosome 15q deletions.
• Hypotonia ,short stature, obesity, small hands
and feet,hypogonadism.
• Angelman’s- ataxia and inappropriate
laughter(happy puppets).
 Diagnosis of genetic disease
• Prenatal –amniocentesis , chorionoc villus
biopsy, umbilical chord blood sampling.
• Postnatal- southern blot, PCR,FISH.
 Medical Genetics (cont.)
Mitochondrial inheritance
• This type of inheritance
applies to genes in
mitochondrial DNA
• Mitochondrial disorders
can appear in every
generation of a family and
can affect both males and
females, but fathers do
not pass mitochondrial
traits to their children.
• E.g. Leber's hereditary
optic neuropathy (LHON)

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 LYON HYPOTHESIS

• 1961 English geneticist Mary Lyon proposed

this hypothesis to describe X inactivation
• Consists of 5 tenants
– 1. Condensed X chromosome is genetically
inactive

– 2. X inactivation in humans occurs early in

development when embryo consists of about 32
cells. 1 or 2 days following fertilization
 5 TENANTS OF LYON HYPOTHESIS

• 3. At this stage in each of the 32 cells one

of the X chromosomes is randomly
inactivated
• 4. Inactivation is mitotically stable
• 5. Net effect of this is to equalize
phenotypes in males and females for genes
that are carried on the X chromosome
 Human Chromosomes
• One X chromosome in females is inactivated
early in embryonic development.
 X REACTIVATION IN FEMALES
• In the female fetus future germ cells undergo
Lyonization along with somatic cells at the 32 cell
stage

• Following differentiation of female fetus, the

inactivated X chromosomes are reactivated during
female gametogenesis

• When germ cells develop into oocytes and enter

meiosis their inactivated X chromosomes become
reactivated so that every egg produced has an
activated X chromosome prior to fertilization
 X REACTIVATION IN MALES
• XXY Klinefelter males also reactivate the second X
chromosome during gametogenisis

• The presence of an extra X chromosome during

early puberty causes death of male germ cells and
testicular atrophy

• This leads to low levels of testosterone