dosage compensation in human genetics.pptx

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: F irst, a twofold up-regulation in the expression of X-linked gene in males S econd, a twofold down-regulation of genes on each of the two X chromosomes in female s 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) C alico-cat ii) T ortoise-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 paterna l 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

8. 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.

9. . 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.

10. 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 .

11. 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 .

12. 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 I DC , 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