Skewed X-chromosome inactivation (skewed X-inactivation) occurs when the X-inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated. It is usually defined as one allele being found on the active X chromosome in over 75% of cells, and extreme skewing is when over 90% of cells have inactivated the same X chromosome. It can be caused by primary nonrandom inactivation, either by chance due to a small cell pool or directed by genes, or by secondary nonrandom inactivation, which occurs by selection.
X-chromosome inactivation occurs in females to provide dosage compensation between the sexes. If females kept both X chromosomes active, they would have twice the number of active X genes than males, who only have one copy of the X chromosome. At approximately the time of embryonic implantation, one of the two X chromosomes in each cell of the female embryo is randomly selected for inactivation. Cells then undergo transcriptional and epigenetic changes to ensure this inactivation is permanent (such as methylation and being modified into Barr bodies). All progeny from these initial cells will maintain the inactivation of the same chromosome, resulting in a phenotypic mosaic pattern of cells in females although not a genotypic mosaic.
Most females will have some levels of skewing. It is relatively common in adult females; around 35% of women have a skewed ratio over 70:30, and 7% of women have an extreme skewed ratio of over 90:10. This is of medical significance, due to the potential for the expression of disease genes present on the X chromosome that are normally not expressed due to random X-inactivation.
Causes
Primary nonrandom inactivation
Nonrandom X-inactivation leads to skewed X-inactivation. Nonrandom X-inactivation can be caused by chance or directed by genes. If the initial pool of cells in which X-inactivation occurs is small, chance can cause skewing to occur in some individuals by causing a bigger proportion of the initial cell pool to inactivate one X chromosome. A reduction in the size of this initial cell pool would increase the likelihood of skewing occurring. This skewing can then be inherited by progeny cells, or increased by secondary selection.
The X-chromosome controlling element (Xce) gene in mice has been found to influence genetically mediated skewing. It is unknown whether a similar gene plays a role in human X-inactivation, although a 2008 study found that skewing in humans is mostly caused by secondary events rather than a genetic tendency.
There is a much higher concordance rate in genetically identical (monozygotic) twins compared to non-identical (dizygotic) twins, which suggests a strong genetic input. A 10% difference in the skewing of genetically identical twins did exist however, so there are other contributing factors outside of genetics alone. It is difficult to identify primary nonrandom inactivation in humans, as early cell selection occurs in the embryo. Mutation and imprinting of the XIST gene, a part of the X-inactivation centre, can result in skewing. This is rare in humans.
Xce
Skewed X-inactivation in mice is controlled by the Xce gene on the X chromosome. Xce acts in cis, which means that it acts upon the chromosome from which it was transcribed. There are four alleles of Xce, labeled a, b, c, and d. Each allele has a different likelihood of inactivation, with a < b < c < d, where d is the most likely to remain active and a is the least likely. The strength differences between the four alleles are likely due to variations in the number of binding sites for a crucial actor in inactivation. The specific transfactor is not known currently.
Homozygotic mouse cells will have roughly even levels of inactivation due to both alleles having equal chance of being inactivated. For example, a mouse with the genotype dd will have an inactivation ratio very close to 50:50. Heterozygotes, will experience greater levels of skewing due to the differing inactivation likelihood of the two alleles. A mouse cell with the Xce genotype ad will have a greater number of the a-carrying than d-carrying X chromosomes inactivated, because the d-carrying X chromosome is less likely to be inactivated.
There are two theories on the mechanism Xce uses to affect inactivation. The first is that genomic differences in the Xce alleles alter the sequence of the long non-coding RNA that is an integral part of X chromosome inactivation. The second is that Xce acts as a binding site for dosage factors that will affect XIST gene and Tsix expression (long non-coding RNAs involved in X chromosome inactivation).