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CHAPTER 1

DNA NUCLEOSOME

At the end of the lecture, students


should be able to:
Describe DNA location in Chromosomes
Describe the Lowest Level of Chromosome

Organization
Differentiate Chromosomes and Chromatin
Describe how different levels of chromation
organization allows chromosome to be fitted
inside nucleus
Differentiate heterochromatin (constitutive
and facultative) and euchromatin

Structure and organization of DNA in


the nucleus of a human cell

Lets refresh your genetics


knowledge...

The Chromosome Theory of


Inheritance
Chromosomes are discrete physical entities
that carry genes
Autosomes occur in pairs in a given individual
(not the X or the Y chromosome)
Sex chromosomes are identified as X and Y
Females have two X chromosomes
Males have one X and one Y chromosome

Human chromosome 22 autosomes +


1 sex chromosome (XX/XY)

Genetic Blueprints for Cells Are Organized


Into Chromosomes
The plans for making cells are coded in DNA
DNA is organized into giant molecules called

chromosomes

Each chromosome is a single DNA molecule

containing many genes


Each gene gives the directions for making 1
protein
In humans each chromosome has approximately
2000 genes (46,000 genes)

Location of Genes on a Chromosome


Every gene has its place, or locus, on

a chromosome
Genotype is the combination of
alleles found in an organism
Phenotype is the visible expression of
the genotype
Wild-type phenotype is the most
common or generally accepted
standard
Mutant alleles are usually recessive

Location of Genes on a Chromosome

All cellular genes are made of DNA arranged


in a double helix
The sequence of

nucleotides in a gene is a
genetic code that carries
the information for
making an RNA
A change in the
sequence of bases
constitutes and
mutation, which can
change the sequence of
amino acids in the genes
polypeptide product

Chromosome parts
Chromosomes have distinct

parts

Centromeres:
Hold duplicated chromosomes
together before they are
separated in mitosis
Kinetochore proteins bind to
centromere and attach
chromosome to spindle in
mitosis
Telomeres: ends of

chromosomes: important in
cell aging

Before a Cell Can Divide it Must Duplicate its


Chromosomes
To make a new cell the old cell must duplicate

all its parts


Duplication takes place in interphase

DNA (chromosomes) duplicated in the S subphase


Entire chromosome is duplicated at the same time
The duplicated chromosome remains attached to the
original chromosome by its centromere
The original chromosome and its duplicated partner
are called sister chromatids

Eukaryotic chromosomes
are made of chromatin, a complex of DNA

and associated protein.


Before cell division, the chromatin
condenses, coiling and folding to make a
smaller package.
Each duplicated chromosome consists of
two sister chromatids, which contain
identical copies of the chromosomes DNA.
As the chromosomes condense, the region
where the chromatids connect shrinks to a
narrow area, the centromere.

How does a chromosome fits into a cell


nucleus (10 m in diameter) & perform its
functions?

How does a chromosome fits into a cell


nucleus (10 m in diameter) & perform its
functions?
Chromosomes present as highly extended

nucleoprotein fibers called chromatin


Chromatin
contains
highly
extended
nucleoprotein
fibers
(DNA,
RNA,
associated protein)
Human DNA: average human cell has ~6.4
billion bp of DNA divided among 46
chromosomes (2 meters long) (estimated
based on each base pair is 0.34nm in
length)

How to fit a 2 meter long DNA into a 10m


nucleus?
Nucleosomes - the lowest level of

chromosome organization
DNA + associated proteins
chromatin (nucleoprotein fibers)
Histones are basic positively charged
proteins that are associated with
negatively charged DNA.
Histones help package the DNA into
structural units called nucleosomes

Nucleosome
structure

Roger Kornberg
(1974, Harvard)
proposed that
DNA & histones
are
organized
into repeating
subunits
(nucleosomes)
This assembly
type increased
the
DNA
packing ratio
to 40 fold

Nucleosome
structure

Ionic bonds (Non covalent bond)


holds negatively charged
phosphate backbones of DNA and
positively charged histones

Each nucleosome
consists of a
nucleosome core
particle.
Each particle consists
of eight core
histones (H2A, H2B,
H3, H4) assembled
into an octamer.
The remaining histone
(H1) is called the
linker histone that
binds to the linker
DNA.
Together the core
interact with 148 bp
DNA and the linker
with additional 20 bp
(Total 168 bp DNA)

Chromosomes and Chromatin: Higher


Levels of Chromatin Structure
Lowest structural level of DNA is 10

nm nucleosome core
In EM, see dots 30 nm in diameter
(3X
the
nucleosome
diameter;
chromatin cut in cross-section)
Linker histones & core histones
implicated in higher-order chromatin
structure (fiber-like structure)

Nucleosome beads on a string

Chromosomes and Chromatin: Higher Levels


of Chromatin Structure
Next stage of packaging - 30 nm fiber is

gathered into series of big, supercoiled


loops
Typically, the DNA loops begin & end with
AT-rich sequences of variety of proteins
Included among proteins is type II
topoisomerase that regulates the degree
of DNA supercoiling
They untangle DNA of different loops when
they intertwine
Loops are usually not visible, only revealed
during mitosis

LEVELS OF
CHROMATIN
ORGANIZATION
Double helix DNA

Nucleosome core particle

Nucleosome filament

Chromatin fiber (Packed


nucleosome)
Supercoiled loops
Mitotic chromosome
(Metaphase)

Chromatin

Two types of chromatin after mitosis in

the diffuse interphase condition :and

euchromatin
heterochromatin

Euchromatin
The euchromatin is less intense and

is dispersed

Euchromatin
a lightly packed form
ofchromatin(DNA, RNA and protein) rich
ingeneconcentration
Often under activetranscription.
Most active portion of the genome within the
cell nucleus - 92% of the human genome is
euchromatic,
remainder
is
calledheterochromatin
Euchromatinis

BACK

Heterochromatin
Heterochromatin (10%) remains condensed

throughout interphase and stains intensely,


indicating tighter packing

Heterochromatin
Tightly packed form ofDNA

thepartofachromosomethatis
inactiveingeneexpression (no
transcriptional activity)butmayfunction
in controlling metabolicactivities,
transcription,andcelldivision.
Two types ;
constitutiveheterochromatin
facultative heterochromatin

Constitutive heterochromatin
Exist in compacted state most of the time

and permanently silenced.


Constitutive heterochromatin is usually
repetitive (few genes) and forms structural
functions such as centromeresortelomeres
If an active gene is accidentally moved
adjacently
to
a
constitutive
heterochromatin;
(as
a
result
of
transposition and translocation) they will
become transcriptionally silenced
position effect

Facultative heterochromatin
Is only silenced during certain phase of an

organisms life, it can be activated!


The case of the XX chromosome vs the XY
chromosome (Females have more genes?)
Only one X chromosome is transcriptionally
active; the other one is a heterochromatic clump
called the Barr body

X chromosome inactivation
X chromosome inactivation - Mary Lyon (British

geneticist, 1961) studied inheritance of coat color in


mice has made the following hypothesis:
Heterochromatization of X chromosome in female
mammals occurs during embryo gastrulation;
inactivates genes on X chromosome
It is random in any given cell (could be paternally or
maternally derived X chromosome)
Inactive X chromosome reactivated in germ cells
before meiosis, so both X chromosomes become
euchromatin & active during oogenesis.
Therefore, all gametes get a euchromatic X
chromosome

Mosaicism
Paternal and maternal genes on X

chromosomes are different


Adult females are genetic mosaics (with
different alleles functioning in different cells)
Reflected in the patchwork coloration of
the fur of some mammals (calico cats)
Pigmentation genes in humans are not found
on X chromosome so there are no calico
women.

Mosaicism in calico cats

Mosaicism in color blind women

Mosaicism has been demonstrated in


women who are carriers for red-green color
blindness (patches of retinal cell with
defective color vision among patches of
normal vision)