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