With the publication of Ohno's watershed monograph1, molecular genetic characterization of the mammalian sex chromosomes has radically altered our view of X-chromosome inactivation and the evolutionary conservation of synteny of the mammalian X chromosome (Ohno's law). X inactivation is the dosage compensation mechanism in mammals whereby during embryogenesis of females a single X-chromosome is genetically silenced. Although most genes are subject to X inactivation, some escape. Moreover, during evolution autosomal genes can be added to the X chromosome and later incorporated to different extents into the inactivation system. A recent report by Karin Jegalian and David Page shows that inactivation of individual X-linked genes can evolve independently in different mammalian lineages2. The general correlation between the presence of a functional Y homologue and escape from X inactivation is remarkable; these results confirm the prevailing theory that Y deterioration is the driving evolutionary force behind the dosage compensation mechanism.
The evolution of the dosage compensation mechanism is inextricably interwoven with the evolution of the mammalian sex determination system and the formation of the Y chromosome (Fig. 1). The sex chromosomes started out as a pair of ordinary autosomes. Once the Y chromosome was elected to accumulate factors contributing to male fitness, a series of events was initiated which culminated in a puny, anarchic Y chromosome and a tightly controlled, hierarchically regulated X chromosome. Analogous to the Biblical sequence in which order follows chaos, a dosage compensation mechanism developed in response to the mass destruction of Y-encoded homologues. Genetic isolation of the Y led to the accumulation of recessive mutations (a process known as Müller's ratchet) that, in aggregate, reduced male fitness; this in turn `pressured' the X chromosome to increase its expression. Excessive X-gene expression is presumed to have decreased female fitness until the X-inactivation system evolved to silence the doubly-dosed genes on one of the X chromosomes in females.
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