X Inactivation: Equality Between the Sexes

Basic RGBSince women have two X chromosomes (XX) and men have only one (XY), the body needs a way of ensuring women don’t get a double helping of X chromosome genes. It does this via a clever little mechanism called X inactivation, a process that the embryo undergoes at the 64-128 cell stage. During X inactivation, one X chromosome in each cell is randomly inactivated and remains inactivated in all descendents of that cell. The X inactivation center (Xic), located near the centromere between Xq11.2 and Xq21.1, is where X inactivation is initiated. A region called Xist (X inactivation-specific transcript) is then transcribed.

Xist is a non-coding RNA which coats the chromosome as it is transcribed from the Xic. After this, other gene silencing mechanisms can then occur, such as methylation of 5’ regulatory regions, deacetylation and methylation of histones, and aggregation of heterochromatin-specific DNA-binding proteins. The inactivated X chromosome (Xi) is packaged as heterochromatin, a tightly packed form of DNA, and is now known as a Barr body. The effect of X inactivation is essentially the equalisation of the number of active X-linked genes in males and females, also known as dosage compensation.

Dosage compensation as a result of X inactivation is called the single-active-X principle, and was discovered by English geneticist Mary Lyon (hence why it is also known as Lyonization). An interesting effect of X inactivation is that women show mosaicism for X-linked genes, as the active X chromosome (Xa) differs from cell to cell. Often, mosaicism can only be seen in the lab, for example when cultured cells produce two different forms of an enzyme. Other examples of mosaicism can be directly observed however, such as women who are heterozygous for a mutation that causes an absence of sweat glands. These women have patches of skin with no sweat glands and patches of skin with sweat glands, depending on whether the Xa in the embryonic cell from which the patches were derived was normal or mutated.  It’s also the science behind your favourite tortoiseshell cat (calico).

Despite being called an inactive X chromosome, actually not all of the genes are silenced. Some of the non-silenced genes have functional homologues on the Y chromosome, as the X and Y chromosomes are descended from the same ancestral chromosome. Over time, the Y chromosome lost the function of most of its genes, and gene silencing in the Xi evolved as these gene functions were lost. This explains why homologous genes are not silenced, as inactivation evolved to silence individual genes and blocks of genes as their homologues were lost.

The pseudoautosomal regions (PARp and PARq) are regions found on the tips of both arms of the X chromosome, and are not inactivated during X inactivation. They contain functional homologues with the Y chromosome, which allow the X and Y chromosomes to synapse during meiosis. These are the only regions of the sex chromosomes where crossing over takes place, so genes in these regions exhibit an autosomal pattern of inheritance.

It has been suggested that reactivation of the Xi may occur in some cancers, although there is little evidence to support this hypothesis. In breast cancer, the Barr body is often lost, and two possible reasons for this have been proposed. One idea suggests that an unstable Xi may be reactivated due to decondensation of the heterochromatin; however, there is currently no evidence to support this theory. The other idea suggests that the Xi could be lost, and the Xa duplicated. Both of these ideas have the same result: a double dose of some or all of the X-linked genes. More research into this topic could increase our understanding of cancer development, and could become an area of increased clinical interest over the next few years.

Reference Chaligné R, & Heard E (2014). X-chromosome inactivation in development and cancer. FEBS letters, 588 (15), 2514-22 PMID: 24937141

Photo http://commons.wikimedia.org/wiki/File:XistRNADNAFISH.jpg

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