Genetics by lulzlulz003


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									                 Medical Genetics
No two persons in this world, except the
monozygotic twins, are exactly alike. All of us have
some individuality in physical and biochemical
But some of our physical characters (traits) are
common with the parents and ancestors. A trait
appearing in the next generation is called a family
But if the trait appears in at least three successive
generations of a family it is called a hereditary
character and transmission of several of characters
from generation to generations is called heredity.
Since hereditary characters are transmitted by
the genes of located in the chromosomes, the
branch of biological science dealing with the
study of the principles of heredity is called
 Study of genetics in human subjects is
human genetics.
 If the study is done with a clinical bias for
detection, management and prevention of
genetically inherited diseases it is called
medical genetics.
 Since genes are located in a linear fashion along
the length of the DNA molecules of the
Chromosomes, knowledge about the Chromosomes
is essential to understand the principles of genetics.
A chromosome is made up of a DNA molecule and
associated proteins. Individual chromosomes are
visible under the light microscope only during cell
division, i.e., only when each chromosome becomes
sufficiently thick by being tightly coiled and folded
along its entire length to shorten to a small fraction
of its interphase length.
During interphase individual chromosomes remain
uncoiled at certain regions (to remain invisible as
euchromatin), and remains coiled in certain other
regions (to become visible as chromatin granules or
Each chromosome shows a constricted region, the
centromere or primary constriction which gets attached to
the chromosomal microtubules during cell division.
If the centromere is located at the middle of the length of the
chromosome, it is called a metacentric chromosome.
If the centromere is located at a distance away from the end
but not exactly at its middle, the chromosome is called a
submetacentric one.
In some chromosomes the centromere is nearer one end
rather than its midpoint. Such chromosomes are called
acrocentric ones. Human acrocentric chromosomes show
small masses of chromatin which are attached to their
shorter arms by a narrow stalk called secondary constriction.
This small mass of chromatin is called satellite-body or sat-
In subhuman species centromeres may be seen to be
situated at one end of some chromosomes. Such
chromosomes are called telocentric.
The shorter arm of submetacentric and acrocentric
chromosomes are called p arm (p = Petit = Small) and their
longer arm is called q arm (q / g = Grand = Large).
Each cell of any organism contains a fixed
number of chromosomes, characteristic for
that species.
In human somatic cells this number is 46
and in the gametes it is 23 only.
The chromosome number in a normal
somatic cell is called the diploid number.
That in a gamete cell is called haploid
number since fusion of two haploid cells
during fertilization restores the diploid
The diploid numbers for some common
species are: Dog-78, Horse-66, Guineapig-
64, Cow- 60, Sheep-54, Rabbit- 44, Cat- 38,
and Mosquito- 6.
Each chromosome in a haploid set is unique in size,
position of centromere and location of genes.
In a diploid set there are two pieces of such unique
type of chromosomes. They are called homologous
pair because one of the pair is derived from the
paternal gamete and the other from the maternal
gamete. Hence the chromosomes of a homologous
pair are identical in length, position of the
centromere, and loci of genes.
Of the 23 homologous pairs of chromosomes in a
normal human somatic cell, 22 homologous pairs
regulate the body characters of a person and are
called autosomes.
The members of the other homologous pair are
called sex chromosomes since they primarily
regulate the sex characters of a person.
In females the two sex chromosomes are identical
and are called X chromosomes.
However, in males the sex chromosomes are not
identical; one is longer than the other. The longer
one is called the X chromosome and the shorter one
is the Y chromosome.
Therefore, males are symbolized as 46 XY and
females as 46 XX.
The X chromosome being longer bears more
number of genes all of which are not represented in
the Y chromosome.
The Y chromosome has a strong male sex
determining influence. Its absence induces female
Gonadal development in the embryo; but its
presence induces development of male gonads.
X chromosomes probably do not contain any potent
sex determining gene. For normal development of
the ovary genes should be present in both the p and
q arms of the X chromosome.
Presence of genes in the short arms of both the X
chromosomes is essential for normal female
somatic characters.
                                 Classification of chromosomes
Groups     Chromos    Length      Position         Appearance in Karyograms
           ome Nos.                  of
 Gr. A      1 2 3     Longest      Meta

 Gr.   B     4 5       Long        Sub
 Gr.   C   6 7 8 9    Medium       Sub
              10       sized       Meta
            11 12                 centric
           13 & X

 Gr.   D    13 14     Medium       Acro
             15        sized      centric
                                 with sat-
 Gr.   E    16 17     short      Sub
             18                  meta
                                 but no
                                 16 is
 Gr.   F    19 20     shortest     Meta
Group G    21 22 &    shortest  Acro
              Y                centric
                              with sat
                              body but
                              Y has no
Thus Groups A and F and also Chromosome no 16 are metacentric; Groups D & G are
acrocentric and all the rest are submetacentric. Except Y chromosome all members of D
& G groups bear Sat-bodies.
           Chromomosomal aberrations
Many birth defects, mental deficiencies and
pregnancy wastes are frequently related to
chromosomal disorders. 50% of all spontaneous
abortions during the first trimester and 10% of all
congenital defects are associated with chromosomal
disorders. It is estimated that 3% of pregnancies
result in a child with a genetic disease or defects at
birth. About 10% of all pediatric and adult
hospitalizations involves some kind of genetic
The causes of chromosomal abnormalities are: i)
aberrations in mitosis, ii) aberrations in meiosis, iii)
ionising radiations, iv) exposure of gonads to high
temperatures, v) high maternal age, vi) viral
infections, exposure to chemicals like formaldehyde,
nitrogen mustard, ethyl urethane etc.
In certain diseases called genetic diseases
the genetic component of the individual is
so overwhelming that it expresses itself in a
predictable manner without any
extraordinary environmental challenges.
The genetic diseases fall into one of the
following three categories:
a.Chromosomal disorders ( microscopic
defects)- due to excessive or deficient
genetic material ( numerical or
morphological alterations of chromosomes.
b.Mendelian disordres or single gene
defects (submicroscopic defects)- due to an
abnormal single mutant gene involving one
or both chromosomes of a homologous pair
at a partticular locus.
c.Multifactorial disorders- due to interaction
of multiple genes and multiple exogenous
environmemtal factors.
    Numerical alterations in chromosomes
Numerical alterations may involve all cells of the
body if the error occurs prior to fertilization or only
certain cells of the individual if the error occurs
subsequent to fertilization.
The former variety includes monoploidy, aneuploidy
and polyploidy.
The latter variety includes mosaicism and chimera.
Somatic cells having haploid number of
chromosomes is monoplidy. It is unknown in man
but common in lower plants. Except in male honey
bees it is rare in adult animals.
It is a condition where somatic cells possess
chromosomes in numbers which is in
multiples of the haploid number (but
excepting the diploid number) e.g., triplody,
tetraploidy etc.
It occurs in certain cells under normal
conditions in old age e.g., some liver cells,
mucosal cells of the urinary bladder.
Polyploid cells seen in interphase state
show large nuclei. The condition may arise
due to:
i) During mitosis after each of the
chromosomes has separated into
chromatids the two sets of chromosomes do
not pull apart but remain in the equatorial
region until a nuclear membrane envelopes
both the sets in the same nucleus of a cell.
ii) Fertilization of an ovum by more than
one spermatozoa ( but survival rate of such
zygotes is very poor).
iii) During telophase of mitosis after the
formation of two nuclear envelops around
the chromosomes at each pole of the
dividing cell there may be failure in
cytokinesis. The two nuclear envelops may
subsequently fuse and thus enclose double
the chromosomal complement of the normal
kinds of cells. Failure of such cytokinesis
during meiosis I leads to formation of
gamets with diploid number of
chromosomes. Their subsequent fertilization
with a normal gamet leads to triploidy.
In this condition the number of chromosomes in a
somatic cell is either greater or lesser than the
diploid number; but not in multiples of the haploid
number. Most such hazards take place during
anaphase due to abnormal spindle apparatus
functioning in either mitosis or meiosis.
Aneuploidy may be trisomy or monosomy.
In trisomy a particular chromosome is present in
triplicate instead of the normal homologous pair.
Thus there is one extra chromosome in the cell.
In monosomy a particular chromosome is present
as a lone member instead of the normal
homologous pair. Thus the cell is deficient in one of
the chromosomes.
In tetrasomy the cell contains 4 members of the
same chromosome i.e., two extra chromosomes are
Aneuploidy results from any of the following two
1.Anaphase lag- here after splitting of the centromere
 one member of the pair undergoes normal migration
 to one pole of the dividing cell but the other member
 of the pair fails to migrate to the other pole. Thus one
 of the daughter cells is normal but the other one is
2.Non dysjunction (dysjunction = seperation)- During
 anaphase when the centriole has splitted one or more
 chromosomes may fail to migrate properly due to
 faulty spindle apparatus functioning. Thus both
 members of a particular homologous pair move
 towards the same pole and the other pole receives
 none. This results in one cell having an extra member
 of the homologous pair (trisomy) and the other sister
 cell having a deficiency in that chromosome
   Non dysjunction in gonads during meiosis I
 results in abnormality in all the four resultant
 gamets but if it occurs during meiosis II two
 gamets will be normal and two gamets will be
Non dysjunction during 1st cleavage division of
 the zygote will result in aneuploidy in all cells
 of the foetus and the foetus will be a mosaic of
 trisomic and monosomic cells.
 When non dysjunction occurs during later parts
of the embryonic differentiation only those cells
which are derived from such abnormal mitosis
will show aneuploidy. Hence the person will be
having a milder form of mosaicism of euploid
tissues with aneuplody in some organs and
Fertilization of a normal gamete with an
aneuploid gamete will result in formation of a
aneuploid zygote. Very prolonged prophase of
meiosis I in elderly women possibly favour non
Autosomal nondysjunction is less
 viable particularly when it affects a
 large chromosome. Nature is more
 tolerant to trisomic cells than
 monosomic ones.
Due to absence of all the genes in a
 whole chromosome the cell
 degenerates early. 99% cases of
 monosomy of the sex chromosome
 (Turner’s syndrome cases with 45 XO
 status) result in abortion.
A chimeric individual has two or more
 cell types which differ in their
 cromosomal number because they
 have a different genetic origin. This is
 done usually in experimental studies
 in a laboratory.
It differs from mosaicism since in the
 latter condition all the cells with
 different chromosomal numbers are
 of the same genetic origin.
Morphological alterations in
1.Deletion- Loss of a segment
 ( whole or part of an arm) of a
chromosome. May be terminal or
interstitial. It is comparable to partial
monosomy. Denoted by ‘-’ sign after
the appropriate arm.
2. Duplication- Addition of the
deleted portion of a chromosome to
another homologous chromosome
due to unequal crossing over. There
is duplication of genes. Not seen in
human beings. It is comparable to
partial trisomy. Less harmful than
3. Inversion- Detachment of a segment
of a chromosome and its later union
with the same homologous member
during crossing over in an inverted
position. No loss of genes; but they are
in altered loci. Usually inversion does
not lead to abnormal phenotypes.
Denoted by ‘inv’ sign.
4. Ring chromosome- A chromosome
after deletion at both ends form a ring
due to adherence of the two deleted
ends to each other. Usually it is not
transmitted to the next generation.
Denoted by ‘r’ sign.
5.Isochromosome- The centromere in
stead of normal longitudinal splitting if
splits transversely will form two
metacentric chomosomes of equal
length and each arm of it having
identical genes. Denoted by ‘i’ sign.
Turner’s syndrome (usually 45XO) can
result with 46 chromosomes if the long
arm of one X chromosome forms
6. Translocation- Exchange of
chromosomal segments between
nonhomologous chromosomes.
It may be heterozygous (when only
one member of the chromosome
pairs is involved in exchanging
segments) or homologous (when
both members of the chromosome
pairs are involved in exchanging

If breaks occur at the centromeres of the two
chromosomes and the whole arms of the
chromosomes are exchanged it is called
Robertsonian translocation.
Usually it is seen between D and G groups
and is often heterozygous.
  The long arm of a G group chromosome may
be fused with the long arm of a D group
The fragment formed by fusion of their short
arms is lost because they are without a
centromere. Mothers of translocated Down’s
syndrome babies are usually a carrier of the

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