Some insights into X chromosome inactivation from studies of human cells.

The inactivation of all but one X chromosome in the somatic cells of mammalian females in an important mechanism for regulating X chromosomal genes. Although the molecular basis for the single active X remains to be elucidated, recent studies have provided some insights. Inactivation occurs about the time of implantation, at least in mouse embryos. On the other hand, germ cells from human embryos have two active X chromosomes and may never be subjected to inactivation. As a consequence of X inactivation, one X chromosome becomes the sole determinant of X specified characteristics of the cell, resulting in cellular mosaicism. Transfer of gene products between cells occurs via gap junctions and by pinocytosis so that in heterozygotes carrying X linked mutations, the mutant phenotype may be masked by the presence of cells or normal type. There is considerable evidence that inactivation in the embryo is random with respect to parental origin of the X chromosome, but that selection occurs subsequently, and may lead to elimination of a whole population of cells in the female. Although there is evidence for preferential inactivation of the paternal X in extra-embryonic membranes of rodents, studies in human embryos have not been confirmatory. Analysis of clonal populations from heterozygotes for X chromosome mutations have been used to determine whether a whole X chromosome is inactive or only parts thereof. Individuals with multiple X chromosomes often manifest somatic abnormalities as well as gonadal ones. There is recent evidence that some loci on the short arm may escape inactivation. X inactivation in diploid human cells has been shown to be a very stable process. The silent X, once inactivated, maintains inactivity despite attempts to turn it on. Our recent studies of enzyme activity in cells from a human triploid abortus (69, XXY) with two active chromosomes indicates that the "active chromosomes" are also stably maintained. The presence of two active chromosomes in triploid cells implicates the autosomes in the regulation of X chromosome activity.