Laboratoire de Biométrie et Biologie évolutive, Université Lyon 1, Centre National de la Recherche Scientifique, Villeurbanne F-69622 cedex, France.
Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5346-51. doi: 10.1073/pnas.1116763109. Epub 2012 Mar 5.
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.
女性体细胞 X 染色体失活（XCI）是如何以及为何在哺乳动物中进化的仍然知之甚少。有人提出，XCI 是一种剂量补偿机制，它的进化是为了使雌性（2X）和雄性（1X）的 X 连锁基因的表达水平均等化，而在两性中，X 连锁基因的表达先增加一倍（“大野假说”）。尽管两性之间 X 染色体表达的均等性已经得到明确证实，但对 X 染色体上基因表达水平整体加倍的测试却得出了相互矛盾的结果。然而，性染色体进化过程中基因剂量的变化不应平等地影响所有基因，而应对剂量敏感基因产生更大的影响。我们表明，对于编码大蛋白复合物（≥7 个成员）组成部分的基因——一类预期为剂量敏感的基因——X 连锁基因的表达与复合物内的常染色体基因相似。这些数据支持 XCI 作为一种剂量补偿机制的大野假说，并使我们能够完善 XCI 进化的大野模型。我们还探讨了剂量敏感基因对人类 X 非整倍体表型（如特纳（X0）和克兰费尔特（XXY）综合征）的贡献。人类 X 非整倍体很常见，并且已知其影响较小，因为大多数多余的 X 基因失活，不受非整倍体的影响。只有逃避 XCI 的基因在 X 非整倍体患者中经历剂量变化。我们将剂量敏感性和 XCI 的数据结合起来，计算了 X 非整倍体综合征候选基因的列表。
