Skewed X-Chromosome Inactivation: Cause or Consequence?

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Abstract
X-chromosome inactivation occurs early during female mammalian development to transcriptionally silence one of the two X chromosomes, thereby achieving dosage compensation with males who have only a single X chromosome and the sex-determining Y chromosome ( 1 ). The choice of which X chromosome to inactivate is generally random in somatic tissue; however, once chosen, the inactivation is stably maintained, and the same chromosome is inactivated in all progeny cells. Therefore, females are mosaics of two populations of cells that differ in the X chromosome that is active. For more than three decades, researchers have used this mosaicism as a tool to examine the potential clonal origin of neoplasias in females ( 2 ), since, if the tumor(s) arose from a single cell after the time of X-chromosome inactivation, then it will have the same X chromosome active in all cells. This skewed (nonrandom) pattern of inactivation has been observed in a wide range of neoplastic tissues [ see ( 3 ) for recent review] and can be considered a consequence of the monoclonal origin of the neoplasia. However in this issue of the Journal, Buller et al. ( 4 ) report the finding of an elevated incidence of nonrandom X-chromosome inactivation in the somatic tissue of females with invasive ovarian cancer and BRCA1 mutations.