Chromosomes /certified fixed orthodontic courses by Indian dental academy

CHROMOSOMES

INDIAN DENTAL ACADEMY
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Two chromatids joined together by centromere -- form
one chromosome.
The chromosomes are composed of nucleoprotein
called chromatin. Consists of --DNA, RNA, basic proteins
called histones and non-histone proteins.
Under electron microscope, the chromatin fibre appears
to have a structure like a ‘String of beads’. According to
the nucleosome solenoid model proposed by Kornberg
and Thomas (1974), the beaded string is made of
repeating units called nucleosomes.


•Each nucleosome is a bead-like particle in the chromatin
structure.
•It is made up of two components, namely,a)Central core
b) DNA segment of certain length.
The central core is called
an octamer because it is
made of 8 molecules of
histone proteins
The double stranded DNA
is wound around the
octamer core.
The segment of DNA
molecule in between the
nucleosome (beads) are
called the linker DNA in the
chromatin.
This gives ‘beads on a
string’ appearance to
chromatin fibre.
.

•The string of beads condenses further to produce a 100 Å
thick nucleosome fibre.
•The nucleosome fibre then supercoils to produce a 300350 Å thick solenoid fibre. Solenoid represents structure of
chromatin fibre in the chromosome
Homologus chromosomes:

Sexually reproducing diploid organism develops
from a diploid zygote (2n).

The zygote is formed when a haploid (n) male and a
haploid (n) female gametes fuse at the time of fertilization.
Thus, the diploid individual receives two sets of
chromosomes: one through the male gamete (paternal set)
and the other trough the female gamete (maternal set).

For every chromosome in the paternal set, there is a
similar looking chromosome present in maternal set. Such
similar chromosomes from paternal and maternal sets have
identical gene loci and are called homologous
chromosomes

•The genes for opposing or alternative factors are called as
alleles. They occupy the same locus on homologous
chromosomes e.g. Tall and dwarf represent allelic
forms of the same gene.
•The chromosome constitution of a species is called
karyotype. This karyotype varies with respect to
chromosome number and morphology for every species.
•The Genotype of an individual is his genetic constitution.
The phenotype is the expression of the genotype as a
morphological, biochemical or physiological trait.
The term genome refers to the full DNA content of the
chromosome set.


The human chromosomes:
-The 46 chromosomes of normal human somatic cells
constitute 23 homologous pairs
-One member of each chromosome pair is inherited from the
father; the other from the mother and one of each pair
is transmitted to each child. Twenty-two pairs are
alike in males and females and hence are called
autosomes. The two sex chromosomes, the remaining
pair, differ in male and female and are of major
importance in sex determination


KARYOTYPING
It is a procedure in which chromosomes are stained
and analyzed by microscopic examination and
photographed. Further the chromosomes are cut out from
these photomicrographs and arranged in pairs according
to the standard classification. The complete picture is
called ‘karyotype’

Fig. --: The Paris classification.

I) The original classification - Denver Classification
Devised in 1960 at a meeting of cytogeneticists in Denver,
Colorado.
Distinguished seven chromosome groups identified by the
letters ‘A’ through ‘G’ on the basis of their overall length
and centromere position.
The location of the centromere or primary constriction is a
constant feature of each chromosome.
Human chromosomes can be classified by centromere
position into three types;
1. Metacentric if the centromere is central,
2.Submetacentric if it is somewhat off-center
3.Acrocentric if it is near one end.


Types of metaphase chromosomes. Telocentric chromosomes
are not found in human beings.


II) The Paris classification:
•Devised in 1971 at the Paris conference,
•Identification of chromosomes based on various banding
patterns.
•Today this nomenclature is accepted all over the world.
•According to this, both P and q arms consist of regions
which are numbered 1, 2 and 3, starting from centromere.
The regions are further subdivided into bands so as to give
precise location e.g. RBI (Retinoblastoma) locus is situated
on chromosome 13. Its precise location is 13q 14 i.e. fourth
band on the first region of long arm of chromosome 13.


Application of karyotyping:
1) Clinical diagnosis:
especially indicated, in patients with congenital
malformations involving multiple systems, mental
retardation or in cases of ambiguous genitalia.
2) Gene mapping:
proper localization of human genes to their specific
positions on chromosomes.
3) Role in cancer:
The detection of Philadelphia chromosome in patients of
chronic myelogenous leukemia (CML)
4) Repeated fetal loss:
On chromosome analysis, the couple may reveal a
chromosomal defect in any one of the partner.
Chromosomal aberrations account for a sizeable number of
spontaneous abortions in the first trimester of pregnancy.

5) Prenatal diagnosis:
Chromosome analysis of chorion villous samples and
amniotic cells may reveal a chromosome abnormality in
the fetus warranting medical termination of pregnancy.
6) Polymorphisms:
Minor heritable differences in the banding pattern are
seen, especially for chromosome 1, 9, 16 and Y
chromosomes These polymorphisms may be used to
trace individual chromosome through families. Thus they
can serve as a markers in family studies or for
determination of the source of the abnormal gamete in
chromosome abnormalities


Structure of nucleic acid
Nucleic acid consists of a long chain of molecules
called nucleotides.
Each nucleotide molecule in turn consists of a
nitrogenous base, a five carbon sugar and phosphorus
molecule.
Nucleic acids--two types. Deoxyribonucleic acid or
DNA and ribonucleic acid or RNA
DNA contains sugar called deoxyribose and RNA
contains sugar called ribose
DNA -- mainly found in chromosomes (exception
mitochondrial DNA) and RNA--chiefly found in nucleolus and
in cytoplasm
The nitrogenous bases are of two types – purine and
pyrimidine.
The purine bases are adenine (A) and guanine (G); and the
pyrimidine bases are thymine (T), cytosine (C) and uracil (U).

RNA differs from DNA basically in three respects:
1) It has sugar ribose in place of deoxyribose of
DNA.
2) Of the four bases, three are common in DNA and
RNA. They are adenine, cytosine and guanine. The
fourth base in RNA is uracil instead of thymine in
DNA.
3) RNA molecule is usually single stranded while DNA
has two strands.
Types of RNAs:
They are of three types:
• m RNA – messanger RNA
• t RNA – transfer RNA
• r RNA – ribosomal RNA

Process of information transmission from DNA to RNA
(transcription and translation):
Transcription:
It is a process whereby information is transmitted
from DNA to the messenger RNA


Translation:
It is a process of translating information from mRNA
into protein synthesis.


GENE – A UNIT OF HEREDITY
Mendel during his experiments on garden Peas used
the term ‘Factors’ which an individual receives from his
parents
In 1909 a Danish Botanist, Johansen, introduced the
term ‘gene’ for these factors.
Later in 1910 Morgan from his experiments on
Drosophila showed that ‘genes are parts of chromosome’.
-Until 1977 gene was thought to be a segment of DNA
molecule possessing a code for amino acids sequence of a
polypeptide chain. This model, however appears to be
inadequate to elucidate the precise mechanism of gene
operation.


Normal gene structure:
In genes, coding sequences are split by intervening
sequences.
• The exon-intron patterns of split genes appear to be
strikingly conserved during evolution
• Within exons, alterations in sequence occur slowly,
approximately at the rate of 10-9 substitutions per codon
per generation through natural selection.
• A typical gene contains a ‘promoter’ region, which
extends for about 200 bp upstream of the transcription
start site at nucleotide +1.
-The TATA box is responsible for correctly locating
the site at which transcription starts. Three other
commonly found elements within the promoter
affect
the efficiency of transcription.
- GC box (GGGCGG), which binds the transcription
factor SP1.

-CAAT box (GGCCAATCT), which binds the transcription
factor CTF and NF-1. Normally found around position – 80
relative to the transcription start site.
-Oct box (ATTTGCAT), which binds the transcription factors
Oct 1 and Oct – 2.
•Enhancers are the regions of DNA that operate to stimulate
the basal level of transcription from its promoter
•Response elements induce genes in response to particular
signals.
•Silencers produce negative control where genes are turned
off by the binding of proteins to elements
•Some genes, termed ‘housekeeping genes’, are expressed
in most tissues mot of the time and are responsible for
functions likely to be necessary in any cell.
•The overall level of transcription of a gene is the outcome
of the different influences exerted by the promoter and
enhancers

Code:
In 1971, Nirenberg and Matthaei proved in vitro that
three consecutive bases of mRNA code for a specific amino
acid. This is known as triplet code or codon.
Triplet code:
The basic function of gene --direct synthesis of
proteins.
There are 20 different amino acids in proteins. Stored
within DNA molecule is genetic information in the form of a
triplet code, which is a sequence of three bases that codes
for one amino acid.
As there are four bases A, T, G and C there can be 43 =
64 such combinations. The sequence of these three bases is
called genetic code or codon. For some amino acids there is
more than one triplet code. In such cases codes are
sometimes called degenerate.. Three of the 64 codons are
‘nonsense’ designating termination of message and no amino
acid will be coded.

MUTATION:
It is defined as any change in sequence of genomic
DNA. In the normal course DNA replication is highly
precise, however, any error that involves this process is
copied in subsequent replications.
Mechanism of mutations:- Mutation occurs by any of
the following three mechanisms: Substitution, deletion,
insertion:


Causes of mutation:
1) Radiation:
Ionizing radiation is by far the most potent mutagen
known. The effect of X-ray in increasing the rate of mutation
was first observed by Muller (1927).
2) Chemical mutagenesis:
Many chemicals are known to be carcinogenic; most
of these are now known to be mutagenic as well. The first
example, found by Auerbach in 1941, was mustard gas, an
alkylating agent that produces single base substitution in
DNA.
3) Spontaneous mutations:
Some mutations are spontaneous errors in
replication that evade the proof reading function of the DNA
polymerases that synthesize new polynucleotides at the
replication fork.

Effect of mutations on gene product:
They are as follows:
1) Chain termination mutations:
DNA transcription normally ceases when a
termination codon is reached. A mutation, which creates a
termination codon, can cause premature cessation of
transcription. In another situation, if the mutation destroys
a termination codon then it allows transcription to continue
till the next termination of codon is reached.
2) Splice mutations:
In this, mutation involves a normal mechanism by
which introns are excised and exons are spliced together
during the formation of a messenger RNA. It leads to
complete failure of synthesis of the gene product.
3) Mutations involving regulatory sequences:
Mutations that involve CAT box and TATA box
regions upstream of the structural gene can cause reduced
transcription of sequence.

GENE MAPPING: METHODS TO LOCALIZE GENES ON
CHROMOSOMES
Gene mapping can be broadly divided into two.
1) Chromosome mapping i.e. assigning a particular gene
or a DNA sequence to a specific chromosome.
2) The second is finer piece of information. It includes the
detailed structure of the gene i.e. ‘DNA mapping’.
Chromosome mapping can be achieved by either
a) Somatic cell hybridization or
b) Fluorescent in situ hybridization


a) Somatic cell hybridization:
This has proved rewarding in genetic linkage. In this
technique somatic cells from two different species are
fused together under favourable conditions and
cultured.


when human and mouse cells are cultured together, some
of the cells form heterokaryons (fused cells with separate
nuclei). The nuclei may then fuse to form true hybrid cells.
The hybrid cells continue to proliferate in culture but for
some unknown reasons, the number of human
chromosomes they contain is progressively reduced
The fact that it is the human chromosome, not the mouse
ones, that are preferentially lost is the basis of the
usefulness of somatic cell hybrids for human linkage
studies
For example:Clones of somatic cell hybrids are selected in which there
are certain combinations of human chromosomes, as
shown. The three clones are examined for expression of
given phenotype.

Chromosome
1

2

3

4

5

6

Clone A

+

+

+

+

-

-

Clone B

+

+

-

-

+

+

Clone C

+

-

+

-

+

-

If the phenotype is expressed in all the three clones, its
locus is on chromosome 1; if it is expressed in clones A
and B but not C, its locus is on chromosome 2; and so on
Panel of hybrid clones covering all 24 human
chromosomes (22 autosomes, X and Y) are available, so it
is usually unnecessary to make new hybrids to look for
linkage

2) Fluorescent in situ hybridization (FISH)
This has revolutionized the concept of
chromosome analysis.
It is based upon the unique ability of a portion of
single stranded DNA, the probe to anneal or hybridize
with its complementary target DNA sequence located in
the genome.
This probe is conjugated with a fluorescent label
and hence can be visualized under uv light.
Various types of chromosome specific probes can
be used. Some of them are specific for the centromere of
chromosome or for a particular portion of a chromosome.
On application to a metaphase spread this probe
hybridizes to that chromosome.


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