Zoology genetics topic

1. Dosage compensation

2. • Dosage compensation refers to equalize the copy number of sex chromosome linked
genes in the in males and females of a species .
• . The two sexes differ in the copy number of X-linked genes and this imbalance
presents the organism with a problem . This can lead to an imbalance in the amount of
gene products (RNAs and proteins), which would, in turn, require differences in
metabolic control and other cellular processes.
• To avoid this, dosage compensation mechanisms have evolved that balance the level of
X-linked gene products between the sexes.
• There are three general methods by which this can be performed:
First, a twofold up-regulation in the expression of X-linked gene in males
Second, a twofold down-regulation of genes on each of the two X chromosomes in females
Third , the complete inactivation of one of the two X chromosomes in females.
The first strategy has been adopted in the fruit fly, Drosophila ,the second in the
worm Caenorhabditis elegans , and, it now seems, both

3. Dosage compensation in Mammals
The Lyon Hypothesis :
Proposed independently by Mary Lyon and Liane Russell(1961)
It is about one of the mechanism through which the effective dosage of X linked
genes of the two sexes is made equal or nearly so in mammals , because females
have double dose of X -linked genes as compared to males .
According to Lyon hypothesis as proposed by M . Lyon
1.In normal mammalian females, one of the two X’s is genetically inactive in the
somatic cells (single active X-hypothesis).
2. Inactivation is random i.e., irrespective of paternal and maternal origin (random
inactivation).
3. The inactivation occurs during early ontogeny (early ontogenic
differentiation) and particular X which has thus become inactivated, remains
inactive in all the succeeding cell generation (fixed differentiation

4. The genetically inactive X- chromosome or condensed X-chromosome is called
hetero-pycnotic X-chromosome or heterochromatin or sex-chromatin body or
Barr body (according to the name of the geneticist M. L. Barr who first observed
it) or Drum-stick (according to the shape of the inactive X-chromosome).
The inactivation of an X-chromosome into a Bar body is sometimes referred to as
lyonization .
The X-inactivation is generalized as per the “n – 1 rule,” which states that if an
individual has n X chromosomes, then n – 1 will be inactivated (Ohno 1967)
Lyon hypothesis was given on the basis of observations of female mice
heterozygous for X-linked coat colour genes which showed mottled
phenotype (mosaic phenotype )that is possible only due to random
inactivation of X-chromosomes .
Other evidences supporting random X-inactivation are mosaic patterns in
i) Calico-cat ii) Tortoise-shell cat
Such X-linked coat colour patterns do not occur in male cats .
Exceptional male “calico” is XXY.

5. Two especially interesting examples from human beings that support
random inactivation of X-chromosomes are :
I)Red green colour blindness ii)Anhidrotic ectodermal dysplasia
Both are x-linked recessive disorders .
Red green colour blindness-hemizygous males are fully colour blind
.However heterozygous females display mosaic retinas with patches of
defective colour and surrounding areas with normal colour perception.
Anhidrotic ectodermal dysplasia-Hemizygous males show absence of
teeth , sparse hair growth and lack of sweat glands .
Heterozygous females for this disorder have random patterns of tissue
with and without sweat glands .

6. X Inactivation Is Developmentally Regulated
X inactivation in female mammals is developmentally regulated .Normally there is an
equal probability that cells will either inactivate maternal X-chromosome (Xm) or
paternal X-chromosome (Xp).
Exceptions to this are ,imprinted X inactivation in marsupials and in early
preimplantation mouse embryos, in which it is always Xp that is inactivated.
In marsupials imprinted Xp inactivation occurs throughout.
In the latter case, imprinted Xp inactivation is maintained in the first differentiating
lineages, namely, the extraembryonic trophectoderm (TE) and primitive endoderm
(PE) cells, but the inactive X is reactivated in the inner cell mass (ICM) cells that give
rise to the embryo. Reversal of X inactivation also occurs in developing primordial
germ cells (PGCs), ensuring the X chromosome is again active in the gamete.
.

7. Some Genes Escape X Inactivation
X inactivation affects most of the X chromosome, but some
genes escape silencing (Berletch et al. 2011). These include
genes within a small region on the X chromosome that pairs
with the Y chromosome during male meiosis, referred to as the
PAR or XY pairing region Genes located in this region do not
require dosage compensation as two copies are present in both
males and females

9. • Metatherian mammals (marsupials) use only the imprinted mode. Some
eutherian mammals (e.g., mouse) use the imprinted mode in
extraembryonic lineages and the random mode in the embryo proper .
• Other species, notably rabbit and human, show only random X inactivation
(Okamoto et al. 2011).
• This variation may be linked, in part, to differences in the timing of
embryonic genome activation, which in mouse occurs relatively early, at the
two-cell stage, compared with the four- to eight-cell stages in humans.

10. . X Inactivation Is Regulated by a Master Switch Locus:
• Classical genetic studies showed that X inactivation is mediated by a single cis-acting master
switch locus, referred to as the X inactivation center (Xic).It is about 1MB(10 lakh)base pairs
in length and is known to contain several putative regulatory units and four genes .The key
gene within the Xic that regulates inactivation is Xist (X-inactive specific transcript ) gene .
• This gene produces a large noncoding RNA termed Xist (X-inactive-specific transcript) which
lacks extended Open reading frame (ORF)and thus has the unique property of binding
in cis and accumulating along the entire length of the chromosome from which it is
transcribed . Coating of the chromosome with Xist RNA provides the trigger for X-
chromosome silencing, through Xist-mediated recruitment of chromatin modifying
complexes .
• It also prevents acetylation and demethylation of DNA and thus promotes condensation
/inactivation
• A second noncoding RNA, Tsix, is also located in the Xic region (Lee et al. 1999) and plays
a key role in regulating Xist expression. Tsix overlaps with the Xist gene, but is
transcribed in the antisense direction; hence, its name is Xist spelled backwards.

11. Dosage compensation in Drosophila
• Mechanism of Dosage compensation in Drosophila differs considerably from
that in mammals.
• Instead of X-inactivation as observed in mammals there is hyperactivation of x-
linked genes in males as compared to females .
• At least four autosomal genes with mle ( maleless ) as the well known one are
involved in regulation of dosage compensation .
• All these autosomal genes are under the control of a single master switch gene
Sxl , located on X-chromosome that induces female differentiation during sex
determination .

12. • According to a well accepted model about dosage compensation in Drosophila mle,
encodes a protein that binds to numerous sites along the X-chromosome
,causing enhancement of its genetic expression.
• Products of other three autosomal genes also participate in and are required
for mle binding.
• The activity of master switch Sxl gene which itself is influenced by X/AA ratio plays an
important role during dosage compensation .
• In XY flies Sxl is inactive ,therefore autosomal genes are activated thus causing enhanced X-
chromosome activity/expression.
• On other hand Sxl gene is active in XX females and functions to inactivate one or more
autosomal genes presumably mle.
• Dampening of autosomal genes thus prevent the double gene expression of X-linked genes
in females .

13. Dosage compensation in Caenorhabditis elegans
• In XX hermaphrodite C. elegans worms dosage compensation involves
to downregulate the expression both X chromosomes two-fold.
• It is achieved by the hermaphrodite specific dosage compensation
complex (DCC) which binds to both X chromosomes to downregulate X-
linked gene expression in hermaphrodites.
•
• Condensin IDC, a subcomplex within the DCC, causes condensation
/compaction of the X-chromosomes which prevents binding of RNA poly
.II to X- linked genes thus repress their transcription .
• Hermaphrodite worm =5 pairs autosomes +XX
• Males =5 pairs autosomes +X0