Sex Chromosomes

Question 1

The normal human chromosome complement consists of how many chromosomes?

Answer 1

46 Chromosomes (23 pairs)

Question 2

How many pairs of autosomes does the normal human chromosome complement contain?

Answer 2

22 pairs of autosomes (numbered 1-22)

Question 3

How many pairs of sex chromosomes does the normal human chromosome complement contain?

Answer 3

1 pair of sex chromosomes (XX in females, XY in males).

Question 4

Describe the X chromosome.

Answer 4

The X chromosome consits of 153Mb and contains 195 known geni loci. There are far more genes carried on the X chromosome than the Y chromosome.

Question 5

Describe the Y chromosome.

Answer 5

The Y chromosome consists of 50Mb and contains around 13 known loci (4 in common with X). There are far more genes carried on the X chromosome than the Y chromosome.

Question 6

Compare the X and Y chromosomes.

Answer 6

The X chromosome consits of 153Mb and contains 195 known geni loci.

The Y chromosome consists of 50Mb and contains around 13 known loci (4 in common with X).

There are far more genes carried on the X chromosome than the Y chromosome.

Question 7

What is dosage disequilibrium and what purpose does it serve?

Answer 7

Females carry 2 copies of the genes on the X chromosomes, males have only one.

If both copies of the X chromosome were transcribed then females would have twice the dosage of these gene products as men.

X inactivation rebalances this by ‘switching off’ one copy of the X in females.

Question 8

Describe the behaviour of the X and Y chromosomes at meiosis.

Answer 8

The X and Y chromosomes share a common sequence at the tip of the short arm. This common region is called the pseudoautosomal region (PAR1). There is a second PAR at the tip of the long arm (PAR2).

At meiosis the X and Y chromosomes are only able to synapse across the PARs. The rest of the X and Y remain unpaired.

Regions of asynapsis are not usually tolerated at meiosis so the X and Y pair form the sex vesicle.

Question 9

What common region is found at the tip of the short arms of the X and Y chromosomes?

Answer 9

The X and Y chromosomes share a common sequence at the tip of the short arm. This common region is called the pseudoautosomal region (PAR1). There is a second PAR at the tip of the long arm (PAR2)

Question 10

At meiosis what regions of the X and Y chromosomes are able to synapse?

Answer 10

At meiosis the X and Y chromosomes are only able to synapse across the PARs. The rest of the X and Y remain unpaired.

Question 11

Why does the sex vesicle form at meiosis?

Answer 11

At meiosis the X and Y chromosomes are only able to synapse across the PARs. The rest of the X and Y remain unpaired.

Regions of asynapsis are not usually tolerated at meiosis so the X and Y pair form the sex vesicle.

Question 12

Describe the structure of the X and Y pseudoautosomal regions (PARs).

Answer 12

There is a 2.6Mb pseudoautosomal regions at the Xp and Yp telomeric regions. This is the region of X and Y that synapses during meiosis. This is also a region that does not undergo X inactivation. This region includes the SHOX gene which is a candidate gene for short stature. There is a second pseudoautosomal region at the end of the long arm of the X and Y chromosome.

Question 13

Describe the most important regions of the X chromosome.

Answer 13

Xp11.2-p22.1 - disruption of this region is associated with ovarian failure (gonadal dysgenesis).

Xq13 - this is the X inactivation centre which harbours a gene called XIST.

Xq13-q26 (about 2/3rds of the long arm of the X chromosome) - this is a critical region for ovarian function. Breakpoints within this region in a balanced X:autosomal translocation are associated with gonadal insufficiency (unless the breakpoint falls into one very small region at Xq22).

Question 14

What is disruption of the Xp11.2-p22.1 region associated with?

Answer 14

Xp11.2-p22.1 - disruption of this region is associated with ovarian failure (gonadal dysgenesis).

Question 15

At what chromosomal location can the X inactivation centre be found?

Answer 15

Xq13 - this is the X inactivation centre which harbours a gene called XIST.

Question 16

What will be the likely outcome of breakpoints in the Xq13-q26 region?

Answer 16

Xq13-q26 (about 2/3rds of the long arm of the X chromosome) - this is a critical region for ovarian function. Breakpoints within this region in a balanced X:autosomal translocation are associated with gonadal insufficiency (unless the breakpoint falls into one very small region at Xq22).

Question 17

Describe the structure of the Y chromosome.

Answer 17

Proximal to the PAR on the short arm of the Y chromosome is the one improtant gene on the Y chromosme, this is called SRY and this is the Testis Determining Factor (TDF).

In proximal Yq (just below the centromere) is the gonadoblastoma specific region containing a gene that is currently known as GBY (not yet positively identified). There are also several genes in the proximal Yq region that are associated with infertility.

The distal part of the long arm of the Y chromosome is heterochromatic. It is non-coding and varies in length. It is Q band and C band positive and is DAPI bright on FISH.

Question 18

What is the 1 important gene on the Y chromosome and at what chromosomal location is it found?

Answer 18

Proximal to the PAR on the short arm of the Y chromosome is the one improtant gene on the Y chromosme, this is called SRY and this is the Testis Determining Factor (TDF).

Question 19

What regions and genes are contained within the proximal Yq region.

Answer 19

In proximal Yq (just below the centromere) is the gonadoblastoma specific region containing a gene that is currently known as GBY (not yet positively identified). There are also several genes in the proximal Yq region that are associated with infertility.

Question 20

Describe the distal part of the long arm of the Y chromosome.

Answer 20

The distal part of the long arm of the Y chromosome is heterochromatic. It is non-coding and varies in length. It is Q band and C band positive and is DAPI bright on FISH.

Question 21

What is the purpose of X inactivation?

Answer 21

X inactivation rebalances the dosage of X chromosome expression in females by ‘switching off’ one copy of the X in females.

In very early development the presence of two active X chromosomes is essential for normal female development.

X inactivation is not complete. The pseudoautosomal regions escape inactivation, as do a small number of other genes scattered throughout the rest of the X.

Question 22

Is X inactivation in females complete?

Answer 22

X inactivation is not complete. The pseudoautosomal regions escape inactivation, as do a small number of other genes scattered throughout the rest of the X.

Question 23

What is X inactivation also known as?

Answer 23

X inactivation is also known as Lyonisation (because it was first described by Mary Lyon).

Question 24

Why is the inactive X in a cell often referred to as the ‘Barr body’?

Answer 24

The inactive X is late replicating. It remains condensed in the interphase nucleus and as a result is darker staining. As a result, it is often referred to as the Barr body.

Question 25

At what stage of embryogenesis does X inactivation occur?

Answer 25

X inactivation occurs at the 5000 cell stage of embryogenesis which is 2 weeks post fertilization.

Question 26

True or False? X inactivation occurs randomly from cell to cell.

Answer 26

True. X inactivation occurs randomly from cell to cell. However, once established all daughter cells retain the same pattern of inactivation as their progenitor. This explains the patchy coat colour in Tortoiseshell cats - a coat colour allele is expressed only from the active X chromosome.

Question 27

Describe the X inactivation centre (XIC). How does it influence the initiation of X inactivation?

Answer 27

The XIC is at Xq13. The critical gene is called XIST (X inactive specific transcript). In order for X inactivation to be initiated two (or more) copies of XIST must be present in the cell. XIST is transcribed into a RNA molecule which coats the X chromosome and initiates inactivation. Inactivation spreads through the X chromosome from the XIC. The inactive X becomes genetically inactive and replicates later in the cycle. XIST is essential for the establishment of X inactivation. Other epigenetic changes - methylation and histone acetylation - are involved in the maintenance of X inactivation.

Question 28

What is the critical gene in the X inactivation centre (XIC) called?

Answer 28

The critical gene is called XIST (X inactive specific transcript).

Question 29

Briefly describe the mechanism behind X inactivation.

Answer 29

The X inactivation centre (XIC) is vital for the process of X inactivation. The XIC is at Xq13. The critical gene is called XIST (X inactive specific transcript). In order for X inactivation to be initiated two (or more) copies of XIST must be present in the cell. XIST is transcribed into a RNA molecule which coats the X chromosome and initiates inactivation. Inactivation spreads through the X chromosome from the XIC. The inactive X becomes genetically inactive and replicates later in the cycle. XIST is essential for the establishment of X inactivation. Other epigenetic changes - methylation and histone acetylation - are involved in the maintenance of X inactivation.

Question 30

What other epigenetic changes are involved in the maintenance of X inactivation?

Answer 30

Other epigenetic changes - methylation and histone acetylation - are involved in the maintenance of X inactivation.

Question 31

True or false? XIST is essential for the MAINTENANCE of X inactivation.

Answer 31

False. XIST is essential for the INITIATION of X inactivation but not for the maintenance of X inactivation. Other epigenetic changes - methylation and histone acetylation - are involved in the maintenance of X inactivation.

Question 32

What might be the consequence of the formation of a derivative X;autosome chromosome translocation that includes the XIC?

Answer 32

If a derivative X;autosome chromosome includes the XIC then that derivative chromosome can be inactivated.

If inactivation occurs in that derivative chromosome then the inactivation can spread from the X material into the attached autosome.

If a derivarive X;autosome does not carry the XIC then the X chromosome material in that chromosome cannot be inactivated.

Question 33

Consider the case of a carrier of a balanced X;autosome rearrangement who carries one normal X chromosome and two segments of X chromosome split between two derivative chromosomes (derX and der21) - only one of which has an XIC. What might be the outcome of such a rearrangement?

Answer 33

At the 5000 cell stage random X inactivation will take place.

In cells where the normal X is inactivated the two segments of X remaining active will equate to one whole X chromosome. This results in functional balance for the X chromosome and viability.

In cells where the derivative X is inactivated then the normal X in addition to the segment of X chromosome material present on the derivative chromosome 21 will remain active. This equates to a functional overdose of the genes from Xq21-Xqter. In addition, the segment of chromosome 21 material present on the derivative X chromosome is also inactivated. This equates to effective monosomy for the distal part of chromosome 21. Such a cell will be non-viable.

The non-viable cells will fail to divide. The majority of cells within the body will be derived from the cells with inactivation of the normal X chromosome. This results in a pattern of non-random X inactivation.

In balanced X;autosome translocation carriers there is normally a pattern of non-random X inactivation with inactivation of the normal X.

Non-random X inactivation may result in the expression of sex-linked disorders in females. For example, if the breakpoint on the X coincides with a significant gene (as you are getting the whole X inactivated and the separate parts of the X expressed you are dependant on there being no problems with expression from the two separate parts of X). There are rare examples of females affected with DMD who have balanced rearrangements with a breakpoint at Xp21.2 within the dystrophin gene.

Question 34

What are the potential consequenced of non-random X inactivation?

Answer 34

Non-random X inactivation may result in the expression of sex-linked disorders in females. For example, if the breakpoint on the X coincides with a significant gene. There are rare examples of females affected with DMD who have balanced rearrangements with a breakpoint at Xp21.2 within the dystrophin gene.

Question 35

What problems are likely to occur with X inactivation in unbalanced carriers of X;autosome translocations?

Answer 35

An unbalanced carrier of an X;autosomal translocation will also demonstrate non-random X inactivation.

Question 36

Consider an unbalanced X;autosome translocation between the q arm of the X chromosome and part of chromosome 21. What may the consequences be?

Answer 36

Cells where the normal X is inactivated will not express the genes from the distal Xq and will also be trisomic for part of chromosome 21. These cells will be non-viable and will fail to divide.

Cells where the abnormal X is inactivated will be viable. Imagining in this example that the unbalanced carrier has 3 copies of the Down Syndrome specific region of Chromosome 21 they will not have Down Syndrome if the abnormal X is inactivated (because the additional 21 material on the derivative X is inactivated). They would however have a Turner phenotype resulting from deletion of part of Xq.