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Chromosome X

X Inactivation

X inactivation consists of the silencing of genes on one of the X chromo somes in the female fetus. This silencing, which results in the absence of protein products from the inactivated genes, restores equal X-linked gene expression between the sexes. So, in the end, females have only one active X chromosome, like males (Figure 1). In the case of individuals with an abnormal number of X chromosomes, such as three X chromosomes, only one X will remain active.

One may wonder then why females do not express deleterious recessive X-linked mutations like males. This is because X inactivation is random, and a female is a mosaic of cells with either her paternal X active or her maternal X active (Figure 1). Thanks to this randomness, female carriers usually have plenty of cells with the normal gene remaining functional. Sometimes, there is even cell selection in carrier females, leading to skewed X inactivation in favor of the normal gene remaining functional. One intriguing feature of X inactivation is that it does not affect all X-linked genes. About 20 percent of genes "escape" X inactivation in humans. With a higher expression level in females than in males, such genes could perhaps play a role in female-specific functions. In males, some of these unusual genes have retained a functionally similar gene on the Y, as remnants of the ancient partnership of the sex chromosomes.

X inactivation was discovered in 1961 by Mary Lyon, a British scientist who studied mice. Thus, another name for this phenomenon is "Lyonization." The physiologic or normal regulation of expression of many genes is at the level of the individual gene. In contrast, X inactivation regulates a whole chromosome that comprises a huge number of genes. Special mechanisms of regulation evolved to initiate X inactivation through the action of a master gene on the X. Once one of the two X chromosomes (maternal or paternal) is randomly chosen to become inactivated in a given fetal cell, it will be faithfully maintained in this state in the progeny of the cell. The stability of the inactivation is mediated by a series of complex molecular changes called epigenetic modifications. X inactivation is lost in only one type of cells, the female germ cells, where both X chromosomes are functional for transmission to the next generation. Thus, X inactivation involves special mechanisms of initiation, maintenance, and reactivation. Much work still needs to be done to fully understand the fascinating roles of the X chromosome and its regulation.

Christine M. Disteche


Miller, Orlando J., and Eeva Therman. Human Chromosomes. New York: Springer-Verlag, 2001.

Nussbaum, Robert L., Rod R. McInnes, and Huntington F. Willard. Thompson & Thompson Genetics in Medicine. Philadelphia, PA: Saunders, 2001.

Wang, Jeremy P., et al. "An Abundance of X-linked Genes Expressed in Spermatogonia." Nature Genetics 27, no. 4 (2001): 422-426.

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Medicine EncyclopediaGenetics in Medicine - Part 4Chromosome X - Role Of The X Chromosome In Sex Differentiation, Sex Chromosome Evolution, The X Chromosome And Diseases