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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 (\u2265 7 members)\u2014a class of genes that is expected to be dosage-sensitive\u2014expression 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.<\/jats:p>","DOI":"10.1073\/pnas.1116763109","type":"journal-article","created":{"date-parts":[[2012,3,6]],"date-time":"2012-03-06T04:33:43Z","timestamp":1331008423000},"page":"5346-5351","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":175,"title":["Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome"],"prefix":"10.1073","volume":"109","author":[{"given":"Eug\u00e9nie","family":"Pessia","sequence":"first","affiliation":[{"name":"Laboratoire de Biom\u00e9trie et Biologie \u00e9volutive, Universit\u00e9 Lyon 1, Centre National de la Recherche Scientifique, Villeurbanne F-69622 cedex, France;"}]},{"given":"Takashi","family":"Makino","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, Graduate School of Life Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan;"},{"name":"Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin 2, Ireland; and"}]},{"given":"Marc","family":"Bailly-Bechet","sequence":"additional","affiliation":[{"name":"Laboratoire de Biom\u00e9trie et Biologie \u00e9volutive, Universit\u00e9 Lyon 1, Centre National de la Recherche Scientifique, Villeurbanne F-69622 cedex, France;"}]},{"given":"Aoife","family":"McLysaght","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, University of Dublin, Trinity College, Dublin 2, Ireland; and"}]},{"given":"Gabriel A. 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