NONRANDOM X-CHROMOSOME INACTIVATION IN MAMMALIAN-CELLS

A salient feature of mammalian X dosage compensation is that X-inactiv ation occurs without regard to the parental origin of either active or inactive X. However, there are variations on the theme of random inac tivation, namely paternal X inactivation in marsupials and in placenta l tissues of some mammals. Whether inactivation is random or paternal seems to depend on the time when this developmental program is initiat ed. As deletions of the X inactivation center (XIC/Xic) and/or the X i nactive specific transcript (XIST/Xist) gene result in failure of cis X-inactivation, mutations in genes from this region might lead to pref erential inactivation of one X chromosome or the other. The Xce locus in the murine Xic is considered a prototype for this model. Recent stu dies suggest that choice involves maintaining the activity of one X, w hile the other(s) by default is programmed to become inactive. Also, c hoice resides within the XIC, so that mutations elsewhere, although pe rhaps able to interfere with cis inactivation, are not likely to affec t the X chromosome from only one parent. Mutations affecting the choic e of active X will be more difficult to detect in humans than in inbre d laboratory mice because of the greater allelic differences between m aternal and paternal X chromosomes; some of these differences predispo se to growth competition between the mosaic cell populations. I sugges t that the skewing of inactivation patterns observed in human females most often occurs after random X inactivation, and is due mainly to ce ll selection favoring alleles that provide a relative growth advantage .