title: Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome.
abstract: How and why female somatic X-chromosome inactivation (XCI) evolved in mammals remains poorly understood. It has been proposed that XCI is a dosage-compensation mechanism that evolved to equalize expression levels of X-linked genes in females (2X) and males (1X), with a prior twofold increase in expression of X-linked genes in both sexes ("Ohno's hypothesis"). Whereas the parity of X chromosome expression between the sexes has been clearly demonstrated, tests for the doubling of expression levels globally along the X chromosome have returned contradictory results. However, changes in gene dosage during sex-chromosome evolution are not expected to impact on all genes equally, and should have greater consequences for dosage-sensitive genes. We show that, for genes encoding components of large protein complexes (≥ 7 members)--a class of genes that is expected to be dosage-sensitive--expression of X-linked genes is similar to that of autosomal genes within the complex. These data support Ohno's hypothesis that XCI acts as a dosage-compensation mechanism, and allow us to refine Ohno's model of XCI evolution. We also explore the contribution of dosage-sensitive genes to X aneuploidy phenotypes in humans, such as Turner (X0) and Klinefelter (XXY) syndromes. X aneuploidy in humans is common and is known to have mild effects because most of the supernumerary X genes are inactivated and not affected by aneuploidy. Only genes escaping XCI experience dosage changes in X-aneuploidy patients. We combined data on dosage sensitivity and XCI to compute a list of candidate genes for X-aneuploidy syndromes.
authors.affiliation: Laboratoire de Biométrie et Biologie évolutive, Université Lyon 1,  Centre National de la Recherche Scientifique, Villeurbanne F-69622 cedex,  France.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Pessia
authors.forename: Takashi
authors.initials: T
authors.lastname: Makino
authors.forename: Marc
authors.initials: M
authors.lastname: Bailly-Bechet
authors.forename: Aoife
authors.initials: A
authors.lastname: McLysaght
authors.forename: Gabriel A B
authors.initials: GA
authors.lastname: Marais
mesh_terms: D000782:Aneuploidy; D000818:Animals; D004303:Dosage Compensation, Genetic; D005260:Female; D006801:Humans; D008297:Male; D049951:X Chromosome Inactivation