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DNA ORGANIZATION AND

DNA PACKAGING

LECTURE 3
OBJECTIVES

Describe how DNA is Describe the correct


packaged levels of
differently in viruses, chromosomal
prokaryotes and structure and
eukaryotes compaction
LEARNING OUTCOMES

To define the genome characteristics in viruses, prokaryotes and eukaryotes

To comprehend about the function and structure of chromosomes and their parts
(centromere, telomere, neucleolar organizing region).

To understand about the chromosomal nomenclature; structural and numerical


chromosome abnormalities

To describe how DNA is organized and packaged in viruses, prokaryotes and


eukaryotes.

To understand about the genomic composition of eukaryotic genome (human genome)

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WHAT IS A GENOME?
 The hereditary basis of every living organism is its genome, a long sequence of
deoxyribonucleic acid (DNA) or RNA that provides the complete set of hereditary
information carried by the organism/virus as well as its individual cells.
 In most living things, the genome is made of a chemical called DNA. The genome
contains GENES, which are packaged in chromosomes and affect specific
characteristics of the organism.
 The word GENOME was used by Hans Winkler a German Botanist as early as
1926.
 The study of genes and their function through understanding the structure of the
genome, including the mapping genes and sequencing of the DNA is termed
GENOMICS.
 The term genomics was coined by Tom Roderick, a geneticist at the Jackson
Laboratory (Bar Harbor, Maine), over beer at a meeting held in Maryland on the
mapping of the human genome in 1986.

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WHAT IS A CHROMOSOME
A chromosome is a package containing a chunk of a genome—that is, it
contains some of an organism's genes.
Chromosomes are made of DNA and protein. Most living things have
chromosomes that are linear, and are kept in the nucleus within the cell.
The important word here is "package": chromosomes help a cell to keep a
large amount of genetic information neat, organized, and compact.
This organization holds true for viruses, prokaryotic and eukaryotic cells.
Packaging DNA into chromosomes serves several important functions
1) chromosome is a compact form of DNA that fits inside the cell.
2) serves to protect DNA from damage
3) only DNA packaged into chromosome can be transmitted to daughter
cells when cell divides
4) regulates gene expression as well as recombination

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CHROMOSOMES
• Chromosomes are made of DNA.
Gene for cystic fibrosis (chromosome 7) • Each contains genes in a linear
order.
• The entire genome represented
by metaphase chromosomes is
called karyotype.
• Human body cells contain 46
chromosomes in 23 pairs – one of
each pair inherited from each
parent
• Chromosome pairs 1 – 22 are
called autosomes (somatic cells).
Gene for sickle cell disease (chromosome • The 23rd pair are called sex
11)
chromosomes (germ cells) :
XX is female, XY is male.
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CHROMOSOME STRUCTURE AND NOMENCLATURE

Somatic cells have diploid complement of


chromosomes i.e. 46.
Germ cells (Gametes: sperm and ova) have
haploid complement i.e 23.
Individual chromosomes are recognized by
o 2 arms, divided at centromere:
 p arm – petit arm
 q arm – long arm
o centromere position (metacentric, sub-
metacentric, acrocentric, telocentric).
Centromeres:
 region where sister chromatids are connected
 made up of repetitive sequences
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CHROMOSOME STRUCTURE AND NOMENCLATURE CON’T

Telomere
DNA and protein cap Light bands
Ensures replication to tip Replicate early in S phase
Tether to nuclear Less condensed chromatin
membrane Transcriptionally active
Gene and GC rich
Short arm
p (petit)
Centromere
Joins sister chromatids

Essential for chromosome segregation at cell division


100s of kilobases of repetitive DNA: some non-specific,
Long arm some chromosome specific
q
Dark (G) bands
Replicate late
Telomere Contain condensed chromatin
AT rich

Chromosomes As Seen At Metaphase During Cell Division


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NOMENCLATURE CONVENTIONS FOR
SPECIFYING SITES IN A CHROMOSOME
1) Each chromosome is assigned a number, with the largest
being assigned number 1.
2) The short arm is designated p and the long arm is
designated q.
3) Regions and bands are numbered consecutively from the
centromere outward along each chromosome arm
4) Chromosome number, arm region number and band
number are written in order and without punctuation or
spacing
Eg:17q12
 The combination of numbers and letters provide a
gene’s “address” on a chromosome.

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THE KARYOTYPE: AN INTERNATIONAL
DESCRIPTION
A normal male chromosome pattern would be described as:
46,XY.
46 = total number of chromosomes
XY = sex chromosome constitution
(XY = male, XX = female).
Any further description would refer to any abnormalities or
variants found (see following slide for examples).

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THE KARYOTYPE: AN INTERNATIONAL
DESCRIPTION
Total number of chromosomes,

Sex chromosome constitution,

Anomalies/variants.
46,XY
47,XX,+21 Trisomy 21 (Down syndrome)
47,XXX Triple X syndrome
69,XXY Triploidy

45,XX,der(13;14)(p11;q11) Robertsonian translocation


46,XY,t(2;4)(p12;q12) Reciprocal translocation

46,XX,del(5)(p25) Deletion tip of chromosome 5


46,XX,dup(2)(p13p22) Duplication of part of short arm Chr 2
46,XY,inv(11)(p15q14) Pericentric inversion chromosome 11
46,XY,fra(X)(q27.3) Fragile X syndrome
46,XY/47,XXY Mosaicism normal/Klinefelter syndrome

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DNA
ORGANIZATION
AND DNA
PACKAGING in

VIRUS

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VIRAL GENOME
Viral Genome also termed the viral
chromosome can be linear or
circular.
The nucleic acid may be dsDNA,
ssDNA, dsRNA or ssRNA, and it may
be a single molecule or several
segments.
Viruses with RNA genome are called
retroviruses
Genome size ranging from 2kb to
2Mb
No special organization needed to
packaged the genetic material into
the cell.
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SOME VIRUS STRUCTURES

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GENOME PACKAGING IN dsDNA VIRUSES (Φ29)
 Large dsDNA bacteriophages,
herpesviruses and adenoviruses encode a
powerful DNA-translocating machinenery
that encapsidates a viral genome into a
preassembled capsid or procapsid
 In most viruses, the packaging machine is
often composed of a dodecamer portal
protein structure, which provides a gate for
DNA entry, and an ATP-driven machine
which is composed of a large (L) and a
small (S) terminase subunit.
 The ATPase activity which fuels the DNA
translocation resides in the L-terminase
subunit, which binds directly to the portal
protein and the S-terminase subunit binds
to packaging initiation sites to prepare for
genome packaging and regulates the
ATPase activity of L-terminase
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DNA
ORGANIZATION
AND DNA
PACKAGING in

PROKARYOTE

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PROKARYOTIC GENOME

The term “prokaryote” means


“primitive nucleus”.
The prokaryotic chromosome is
dispersed within the cell and is not
enclosed by a separate membrane so each bacterial chromosome is packed
tightly in a specific region of the cell (Nucleoid).
For most prokaryotes (ex: the bacterium E. coli), the genetic material is in the
form of a circular, double-stranded DNA molecule.
Although a single type of chromosome is present in the bacteria, they can
have more than one copy of that chromosome.

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PROKARYOTIC GENOME

Some prokaryotes have one or

more small, circular or linear

DNA molecules called plasmids


 Plasmids aren’t part of the nucleoid and often carry non-essential genes

 Can be copied and transmitted between cells

 Can be incorporated into the cell’s chromosomal DNA and reproduced during
cell division
 So the hereditary information contained on a plasmid can be transferred from cell to cell

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PROKARYOTIC GENOME

Most prokaryotes contain


only one copy of each gene (monoploid)
 They are haploid organisms
 Their genomes contain very little non-essential DNA
 In E.coli only 11%

The majority of prokaryotic genomes are composed of


region that contain either genes or regulatory
sequences
 Regulatory sequences determine when certain genes
and the associated cell functions are activated

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E.coli CHROMOSOMES

Prokaryotic genomes are exemplified by the E. coli chromosome.

The bulk of the DNA in E. coli cells consists of a single closed-circular


DNA molecule of length 4.6 million base pairs.

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• Prokaryotes including bacteria
contain the genetic material in a
fairly compact lump, occupying
about one-third of the volume of
the cell.
• Since the genetic material is not
compartmentalized and lies
naked in the cytoplasm, it is
called nucleoid.
• The nucleoid is a folded structure,
containing many supercoiled
loops having many independent
domains.
• There are about 100 domains per
genome and each domain
consists of about 40kb of DNA.
The prokaryotic genome is a
single replicon.
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CHROMOSOMAL DNA IS COMPACTED ~
1000 FOLD TO FIT WITHIN CELLa) A single chromosome of E.Coli
contains about 3x109 Daltons or
about 4.5 x 106bp of DNA. If all
of this DNA were in a circular
structure, it would be 350
micrometer in diameter. But
inside the cell, the chromosome
is coiled to the size of 2
micrometer. Electron
micrographs of E.coli
chromosome suggest a folded
circular structure containing 40-
100 super coiled loops.
b) It is formed by the following
steps i.e. initially circular DNA
binds with the RNA-Protein core
and forms loops.
c) Secondly, the loops form super
coiled structure.
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CHROMOSOMAL DNA IS COMPACTED ~ 1000
FOLD TO FIT WITHIN CELL
d) The interaction between the loops and RNA -
Protein core is not understood. D.E. Pettijohn and
his co-workers showed that the individual
supercoiled loops maintained their supercoiling
independently of one another. Thus, if a single
nick is introduced into one of the loops by limited
DNase action, that loops adopts an expanded
relaxed conformation, but supercoiling in the other
loops is maintained.
e) Limited RNase or protease treatment causes the
partial breakdown of the looped structures without
interfering with the supercoiling. These results
have lead to the conclusion that each of the loops
is a domain, the lateral motion of which is restricted
by an RNA-Protein core complex.

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E.coli CHROMOSOMES

Size
◦ Escherichia coli
~ 4.6 million bp
◦ Cells are typically rod-shaped,
about 2.0 micrometers (μm) long
and 0.25–1.0 μm in diameter
Composition
◦ E.coli ~6000 genes
◦ Genes encoding proteins for related
functions arranged in operons
◦ Intergenic regions represents the
nontranscribed DNA
◦ Single origin of replication (Ori)

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PROKARYOTIC GENE (OPERON) STRUCTURE

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DNA
ORGANIZATION
AND DNA
PACKAGING in

EUKARYOTE

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EUKARYOTIC GENOMES

(Extranuclear Genome)
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HUMAN GENOME

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NUCLEAR GENOME

 Characteristics of eukaryotic nuclear


genome:
• Genome is a double stranded DNA
• Genome arranged in several linear packages called
chromosomes through interactions with several proteins.
The chromosomes in their most condensed
form are called metaphase chromosomes.
The entire genome represented by
metaphase chromosomes is called karyotype.
The number of sets of chromosomes in a
given eukaryotic cell is referred to as the level
of ploidy.
haploid (single), diploid (double), triploid (triple), and
tetraploid (quadruple) sets of chromosomes. Triploid and
tetraploid chromosomes are examples of polyploidy.
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EUKARYOTIC CHROMOSOMES

 Eukaryotic species contain one or more sets of


chromosomes
 Each set is composed of several different linear chromosomes

 The total amount of DNA in eukaryotic species is typically


greater than that in bacterial cells

 Chromosomes in eukaryotes are located in the nucleus


 To fit in there, they must be highly compacted
 This is accomplished by the binding of many proteins
 The DNA-protein complex is termed chromatin

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VARIATIONS IN DNA CONTENT
 Eukaryotic genomes vary
substantially in size
 In many cases, this
variation is not related to
complexity of the species
 For example, there is a two
fold difference in the size of
the genome in two closely
related salamander species
 The difference in the size of
the genome is not because
of extra genes
 Rather, the accumulation
of repetitive DNA
sequences
 These do not
encode proteins
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QUESTIONS
1) The DNA in a bacterial (prokaryotic) chromosome is best described as:
a) a single circular double-helical molecule.
b) a single linear double-helical molecule.
c) a single linear single-stranded molecule.
d) multiple linear double-helical molecules.
e) multiple linear single-stranded molecules.

2) The DNA in a eukaryotic chromosome is best described as:


a) a single circular double-helical molecule.
b) a single linear double-helical molecule.
c) a single linear single-stranded molecule.
d) multiple linear double-helical molecules.
e) multiple linear single-stranded molecules.
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ORGANIZATION OF EUKARYOTIC
CHROMOSOMES
A eukaryotic chromosome contains a long, linear DNA molecule
DNA are organized and packaged with associated proteins into
chromosomes.
Chromosomes undergo dramatic reorganization when cells divide.
Three types of DNA sequences are required for chromosomal
replication and segregation
 Origins of replication
 Centromeres
 Telomeres

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Genes are located between the centromeric and telomeric
regions along the entire chromosome
 A single chromosome usually has a few hundred to several thousand
genes
In lower eukaryotes (such as yeast)
 Genes are relatively small
 They contain primarily the sequences encoding the polypeptides
 ie: Very few introns are present
In higher eukaryotes (such as mammals)
 Genes are long
 They tend to have many introns

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EUKARYOTIC CHROMATIN COMPACTION

 If stretched end to end, a single set of human chromosomes will


be over 1 meter long!
 Yet the cell’s nucleus is only 2 to 4 mm in diameter
 Therefore, the DNA must be tightly compacted to fit

 The compaction of linear DNA in eukaryotic chromosomes


involves interactions between DNA and various proteins
 Proteins bound to DNA are subject to change during the life of the cell
 These changes affect the degree of chromatin compaction

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LEVELS OF DNA PACKING

 1st level: nucleosome

 2nd level: solenoid / chromatin

 3rd level: looped domain

 4th level: metaphase chromosome

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PROTEIN HISTONES AND THE FIRST LEVEL OF PACKING: NUCLEOSOME

 The repeating structural unit within eukaryotic chromatin is the


nucleosome

 It is composed of double-stranded DNA wrapped twice around


an octamer of histone proteins
 An octamer is composed two copies each of four different histones
 146 bp of DNA make 1.65 negative superhelical turns around the
octamer

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Vary in length between 20 to 100 bp,
depending on species and cell type
Diameter of the
nucleosome

 Overall structure of connected nucleosomes resembles “beads on a string”


 This structure shortens the DNA length about seven-fold

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 Histone proteins are basic
 They contain many positively-charged amino acids
 Lysine and arginine
 These bind with the phosphates along the DNA backbone
 There are five types of histones
 H2A, H2B, H3 and H4 are the core histones
 Two of each make up the octamer
 H1 is the linker histone
 Binds to linker DNA
 Also binds to nucleosomes
 But not as tightly as are the core histones

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Play a role in the
organization and compaction
of the chromosome

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SUPERCOILING BEGINS!!!

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http://www.nature.com/nri/journal/v3/n11/images/nri1225-i2.jpg
SECOND LEVEL OF PACKING: SOLENOIDS/CHROMATIN
(NUCLEOSOMES JOIN TO FORM A 30 NM FIBER)
 Nucleosomes associate with each other to form a more compact structure termed the 30
nm fiber
 Histone H1 plays a role in this compaction
 At moderate salt concentrations, H1 is removed

 The result is the classic beads-on-a-string morphology

 At low salt concentrations, H1 remains bound

 Beads associate together into a more compact morphology

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 The 30 nm fiber shortens the total length of DNA another
seven-fold

 Its structure has proven difficult to determine


 The DNA conformation may be substantially altered when extracted
from living cells

 Two models have been proposed


 Solenoid model - H1 histones aggregate causing 6 nucleosomes to
coil together
- stack on top of each other forming the chromatin
fiber

 Three-dimensional zigzag model

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Regular, spiral
configuration
containing six
nucleosomes per turn

Irregular
configuration where
nucleosomes have
little face-to-face
contact

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THIRD LEVEL OF PACKING: LOOPED DOMAINS

 The two events we have discussed so far have shortened the


DNA about 50-fold

 A third level of compaction involves interaction between the 30


nm fiber and the nuclear matrix

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 The nuclear matrix is composed of two parts
• Nuclear lamina
• Internal matrix proteins
10 nm fiber and associated proteins

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 The third mechanism of DNA compaction involves the
formation of radial loop domains

Matrix-attachment
regions
25,000 to
or 200,000 bp
Scaffold-attachment
regions (SARs)

MARs are anchored


to the nuclear matrix,
thus creating radial
loops

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FURTHER COMPACTION OF THE CHROMOSOME

 The attachment of radial loops to the nuclear matrix is


important in two ways
1. It plays a role in gene regulation

2. It serves to organize the chromosomes within the nucleus


 Each chromosome in the nucleus is located in a discrete and
nonoverlapping chromosome territory

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FOURTH LEVEL OF PACKING: METAPHASE CHROMOSOME

Heterochromatin vs Euchromatin
 The cell cycle affects DNA packing, with DNA condensing for
mitosis and meiosis, and decondensing during interphase.
 Chromosomes are most condensed at metaphase, when the
looped domains are further coiled and the chromatic has a
diameter of about 700 nm.
 Non-histone proteins form the scaffold for this additional
condensation.

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 Staining of chromatin using the Giemsa stain reveals two forms:
 Euchromatin –
 Less condensed regions of chromosomes
 Transcriptionally active
 Regions where 30 nm fiber forms radial loop domains
 Heterochromatin
 Tightly compacted regions of chromosomes
 Transcriptionally inactive (in general)
 Radial loop domains compacted even further

 The resulting pattern is called the G-banding pattern.

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There are two types of HETEROCHROMATIN
 Constitutive heterochromatin
 Regions that are always heterochromatic
 Permanently inactive with regard to
transcription
 Facultative heterochromatin
 Regions that can interconvert between
euchromatin and heterochromatin
 Example: Barr body

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METAPHASE CHROMOSOMES

 As cells enter M phase, the level of compaction changes


dramatically
 By the end of prophase, sister chromatids are entirely
heterochromatic
 Two parallel chromatids have an overall diameter of 1,400 nm

 These highly condensed metaphase chromosomes undergo


little gene transcription

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METAPHASE CHROMOSOMES

 In metaphase chromosomes the radial loops are highly


compacted and stay anchored to a scaffold
 The scaffold is formed from the nuclear matrix

 Histones are needed for the compaction of radial loops

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Compaction level
in euchromatin

During interphase
most chromosomal Compaction level
regions are in heterochromatin
euchromatic

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ORGANIZATION OF THE METAPHASE CHROMOSOMES

 Two multiprotein complexes help to form and organize


metaphase chromosomes

 Condensin
 Plays a critical role in chromosome condensation

 Cohesin
 Plays a critical role in sister chromatid alignment

 Both contain a category of proteins called SMC proteins


 Acronym = Structural maintenance of chromosomes
 SMC proteins use energy from ATP and catalyze changes in
chromosome structure
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The number of loops has not changed
However, the diameter of each loop is smaller

During interphase,
condensin is in the
cytoplasm

Condesin binds to
chromosomes and
compacts the
radial loops

Condesin travels
into the nucleus

The condensation of a metaphase chromosome by condensin

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Cohesins along Cohesin at
chromosome arms are centromer is
released degraded

Cohesin
remains at
centromere

The alignment of sister chromatids via cohesin


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QUESTIONS
3) Histones are _______ that are usually associated with _________.
A) acidic proteins; DNA
B) acidic proteins; RNA
C) basic proteins; DNA
D) basic proteins; RNA
E) coenzymes derived from histidine; enzymes
4) The fundamental repeating unit of organization in a eukaryotic chromosome is:
A) the centrosome.
B) the lysosome.
C) the microsome.
D) the nucleosome.
E) the polysome.

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GENOMIC CONTENT

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GENOMIC COMPOSITION (gDNA vs mtDNA)

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THE MITOCHONDRIAL GENOME (mtDNA) - GENOME CHARACTERISTICS

 The mitochondrial genome size is 16.6 Kbp.

 Circular.

 Encodes 37 Genes (2 rRNA, 13 proteins, 22 tRNAs).

 Coding region constitutes 93% of the total genome.

 D-loop is the only non-coding region.

 Consists of HEAVY (12 protein coding genes) and LIGHT (1 protein


coding gene) strands.

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Mitochondrial Genome

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GENE COMPOSITION

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HUMAN NUCLEAR GENOME

 20,000-35,000 genes

 most of the DNA does


NOT encode for a protein
or RNA (is not a gene)

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CLASSES OF NONCODING SEQUENCES

Introns
Regulatory sequences
Highly repetitive sequences:
 Tandemly repetitive
DNA (tandem repeats)
 Interspersed repetitive
DNA
 Telomeres

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NONCODING DNA

NONCODING DNA

Introns Repetitive DNA Regulatory


sequences

Tandemly Repetitive Interspersed


DNA Repetitive DNA

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TANDEM REPEATS
Tandem repeats occur in DNA when a pattern of two or
more nucleotides is repeated and the repetitions are
adjacent to each other
 Form different density band on density gradient
centrifugation (from bulk DNA) -satellite
 Example:
A-T-T-C-G-A-T-T-C-G-A-T-T-C-G
 Tandem repeats:
 SatelliteDNA:
 Microsatellite:

 Minisatellite:
TANDEM REPEATS - SATELLITE DNA
 Unit - 5-300 bp depending on species.
 Repeat - 105- 106 times.
 Location - Generally heterochromatic.
 Examples - Centromeric DNA, telomeric DNA. There are at
least 10 distinct human types of satellite DNA.
TANDEM REPEATS - MICROSATELLITE DNA

 Unit - 2-4 bp (most 2).


 Repeat - on the order of 10-100 times.
 Location - Generally euchromatic.
 Examples - Most useful marker for population level
studies..
TANDEM REPEATS - MINISATELLITE DNA

 Unit - 15-400 bp (average about 20).


 Repeat - Generally 20-50 times (1000-5000 bp long).
 Location - Generally euchromatic.
 Examples - DNA fingerprints. Tandemly repeated but
often in dispersed clusters. Also called VNTR’s (variable
number tandem repeats).
TANDEMLY REPETITIVE DNA CAN CAUSE DISEASES

 Fragile X Syndrome
 “CGG” is repeated hundreds or even thousands of times creating
a “fragile” site on the X chromosome.
 It leads to mental retardation.

 Huntington's Disease
 “CAG” repeat causes a protein to have long stretches of the
amino acid glutamine.
 Leads to a neurological disorder that results in death
INTERSPERSED REPETITIVE DNA

 Interspersed repetitive DNA accounts for 25–40 %


of mammalian DNA.
 They are scattered randomly throughout the
genome.
 The units are 100 – 1000 base pairs long.
 Copies are similar but not identical to each other.
 Interspersed repetitive genes are not stably
integrated in the genome; they move from place
to place.
 They can sometimes mess up good genes
INTERSPERSED REPETITIVE DNA
CON’T
These are:
 Retrotransposons (class I transposable
elements) (copy and paste), copy
themselves to RNA and then back to DNA
(using reverse transcriptase) to integrate
into the genome.
 Transposons (Class II TEs) (cut and paste)
uses transposases to make a staggered
sticky cut.
INTERSPERSED REPETITIVE DNA CON’T

 Retrotransposons are:
 long terminal repeat (LTR) Any transposon flanked
by Long Terminal Repeats. (also called retrovirus-
like elements). None are active in humans, some are
mobile in mice.
 long interspersed nuclear elements (LINEs)
encodes RT and
 short interspersed nuclear elements (SINEs) uses
RT from LINEs. example Alu made up of 350 base
pairs long, recognized by the RE AluI
RENATURATION EXPERIMENTS

 The rate of renaturation of complementary DNA strands


provides a way to distinguish the different types of repetitive
sequences

 The renaturation rate of a particular DNA sequence depends


on the concentration of its complementary partner
 Highly repetitive DNA will be the fastest to renature
 Because there are many copies of complementary sequences
 Unique sequences will be the slowest to renature
 It takes added time for these sequences to find each other

Copyright © 2009 Pearson Education Inc., publishing as Pearson Benjamin Cummings


Copyright © 2009 Pearson Education Inc., publishing as Pearson Benjamin Cummings
60-70% of human
DNA are unique
sequences

Figure 10.13

Copyright © 2009 Pearson Education Inc., publishing as Pearson Benjamin Cummings


TO READ
Karyotype Scaffold Cohesin Heterochromatin

Condensin
Euchromatin acrocentric Pseudogenes

Nucleosome sub-metacentric Satellite telocentric

G-banding
Bead On a String metacentric Alu elements
pattern

variable number
LINE and SINE
Histone Nuclear Lamina tandem repeats
elements
(VNTR's)
Copyright © 2009 Pearson Education Inc., publishing as Pearson Benjamin Cummings
REFERENCES
 Peter J. Russell. 2014. iGenetics: A Molecular Approach (3rd Edition).
Pearson Benjamin Cummings.
 Burton. E. Tropp. 2012. Molecular Biology: Genes to Proteins. (4th
Edition). USA. Jones and Bartlett Learning.
 James D. Watson. 2008. Molecular Biology of the Gene. (6th Edition).
Pearson Publishing.
 Brown T.A. 2007. Genomes 3. (3rd edition). New York. Garland
Science Publishing.
 Robert J. Brooker. 2005. Genetics Analysis and Principles (2nd
Edition). New York. McGraw-Hill.

Copyright © 2009 Pearson Education Inc., publishing as Pearson Benjamin Cummings


THE END

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