Sex chromosomes Flashcards
Features of the X and Y chromosomes
X chromosome 153Mb with ~2000 genes
Y chromosome 59Mb with 50-60 protein coding genes
Share regions of common sequence (pseudoautosomal regions)
Pseudoautosomal regions
PAR1 distal short arm and PAR2 distal long arm
Regions contain ~29 genes
X and Y chromosomes pair only at these sites during meiosis (regions of asynapsis not usually tolerated so form a sex vesicle)
PAR1 = 2.6Mb includes SHOX gene
Regions do not undergo X inactivation
Structure of the X chromosome
Xp11.2-p22.1: Disruption is associated with ovarian failure (gonadal dysgenesis)
Xq13: XIST
Xq13-q26: critical region for ovarian function (translocation breakpoints within this region associated with gonadal insufficiency except q22)
Structure of the Y chromosome
SRY proximal to PAR1 (testis determining factor)
Proximal Yq contains several genes associated with infertility and is the gonadoblastoma specific region (gene not identified)
This gene has has an undefined physiological role in normal males, and thought to predispose dysgenic gonads to develop malignancy when present in females (risk low)
Distal Yq heterochromatic (Q and C band positive, DAPI bright FISH)
What is X inactivation?
mechanism of dosage compensation whereby one X chromosome is transcriptionally silenced
females carry 2 copies of X so if both were transcribed, females would have twice the gene dosage
When is X inactivation initiated?
At the 5000 cell stage (2wk post fertilisation)
Daughter cells retain same pattern of inactivation as progenitor
The presence of two X chromosomes is essential for early normal female development
For inactivation to be initiated, 2 copies of the XIST gene must be present within the cell
How is the inactive X identified cytogenetically?
Replicates late during mitosis and remains condensed in interphase cells
=Barr body
What are the two forms of X inactivation?
- Random
2. Imprinted
What genes regulate X inactivation?
2 antagonistic gene that encode noncoding RNAs XIST and TSIX
XIST expression
Expressed from the inactive X
Only expressed in cells containing at least 2 X chr
Higher expression observed in cells with more X chrs (counting)
How does XIST inactivate the chromosome from which its expressed?
Produces a noncoding RNA that is retained within the nucleus and ‘coats’ the chromosome
Also induces spatial reorganisation of the chr, creating a repressed nuclear compartment depleted of transcriptional machinery
Shown to be necessary and sufficient for inactivation
Whole chromosome silencing involves recruitment of histone variants (macroH2A) and chromatin modifiers
TSIX repression of XIST
Antisense, transcribed in the opposite direction across XIST
Also only acts on the chr from which it is expressed
Inverse relationship between expression of XIST and TSIX
When TSIX expression is reduced, XIST expression increases, leading to inactivation of that X
X;autosome rearrangements and inactivation
If derivative chr includes XIC, it can be inactivated
This may spread to the autosome involved
if the derivative chr doesn’t include the XIC, it cannot be inactivated
Carriers of balanced X;autosome rearrangements
usually show non-random x inactivation of the normal X
If derivative inactivated, can result in monosomy for region of autosome invovled and overdose of genes from X involved in derivative autosome (cells non-viable)
Possible consequence of non-random X inactivation
may result in expression of sex linked disorders in females
e.g. breakpoint in DMD gene
