X inactivation Flashcards
How does X inactivation occur? What gene drives this process?
Initiated by x inactivation centre (XIC) at Xq13.
Is driven by the XIST gene.
Where is the PAR1 region and what function does it serve?
Tip of the X and Y chromosomes (p arms)
PAR1 region pairs at meiosis and can recombine.
What is the sex vesicle?
Structure of the X and Y when they pair at PAR1 at meiosis.
Structure is caused by the chromosomes staying unpaired apart from the tips (PAR1) region.
Is the PAR1 region inactivated?
No.
What important gene does the PAR1 region contain?
The SHOX gene.
What is the process of X inactivation called? When does it happen?
Lyonisation.
Approximately the ~5000 cell stage/2 weeks post fertilisation.
How does XIST inactivate the X? Does it inactivate the entire X?
XIST RNA coats the X, spreading in both directions from the X inactivation center.
No, some areas escape inactivation. PAR1, PAR and Xq21.3 escape inactivation.
Is it always the same X which is inactivated?
Yes and no. The initial choice of which X to inactivate is random. But in the descendant cells from then on, the same X is always inactivated.
What is a Barr body?
The inactivated X when visualised during interphase.
When does the inactive X replicate?
Late on in the cell cycle. It takes on the properties of heterochromatin.
What situation may result in an X-linked recessive disease in a female?
Skewed inactivation - mutant X active in majority of cells.
What are the consequences of X inactivation in females with X chromosome rearrangements?
A patient with a balanced rearrangement may have an abnormal phenotype as they may not be functionally balanced.
A patient with an unbalanced rearrangement may have a normal phenotype as they may be functionally balanced.
Describe how a balanced X:autosome translocation could potentially cause an abnormal phenotype.
If a part of the X chromosome is translocated onto an autosome then the material is no longer under the control of ‘XIST’ and therefore can’t be inactivated.
Likewise the reciprocal segment which has moved onto the X is now on the same chromosome as ‘XIST’ and could be inactivated.
This would cause functional monosomy of the autosome segment and functional disomy of the X segment = abnormal phenotype.
Which is more likely to result in an abnormal phenotype and why (ignoring the autosome segment content).
- X:autosome translocation where the translocated segment from the X is large
- X:autosome translocation where the translocated segment from the X is small
More likely to get an abnormal phenotype if the segment is small.
Because of the random nature of X inactivation, some cells will have the normal X active and combined with the active segment attached to the autosome the cell will have functional X disomy. This is detrimental to the cell and it will die off.
The cells with the ‘normal’ X inactivated will be OK and will mostly go on to produce the fetus.
Describe how an unbalanced X:autosome translocation could result in a clinically normally female?
Selective inactivation of the cell line with an inactive abnormal X.
The derivative X chromosome containing the segment of autosome oils be inactivated and therefore a partial trisomy would be turned into a functional disomy.
Process is variable and unpredictable.
