All mammals compensate for sex differences in numbers of X chromosomes by transcribing only a single X chromosome in cells of both sexes; however, they differ from one another in the details of the compensatory mechanisms. These species variations result from chance mutations, species differences in the staging of developmental events, and interactions between events that occur concurrently. Such variations, which have only recently been appreciated, do not interfere with the strategy of establishing a single active X, but they influence how it is carried out. In an overview of X dosage compensation in human cells, I point out the evolutionary variations. I also argue that it is the single active X that is chosen, rather than inactive ones. Further, I suggest that the initial events in the process-those that precede silencing of future inactive X chromosomes-include randomly choosing the future active X, most likely by repressing its XIST locus.
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