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.

Fig. 1.

X/A expression ratio. (A) In this analysis, 734 X genes and 19,066 autosomal genes are included (Materials and Methods). Expression of X genes is normalized by the median of autosomal gene expression. The median of X/A ratios and associated 95% confidence interval are shown for each tissue. Results for both all genes (black, as in ref. 15) and excluding nonexpressed genes (gray, as in ref. 17) are shown. (B) Here only genes involved in protein complexes are included. For each complex, we computed the median of X gene expression over that of autosomal gene expression. We prepared three groups with similar sample size with increasing protein-complex size in number of proteins: small (2–3 proteins, yellow), medium (4–6 proteins, orange), large (7–120 proteins, brown). For each tissue and complex size category, the median of within-complex X/A ratios and associated 95% confidence interval are shown. In both panels we show the results for a pool of eight tissues (see text). The two green dashed lines indicate expectations with dosage compensation (X/A = 1) and without dosage compensation (X/A = 0.5).

Fig. 2.

X expression and autosomal expression in large protein complexes versus others. For each tissue, we computed the ratio of the median of X gene expression of large complexes (≥ 7 proteins, n = 59) and the median of X gene expression of other protein complexes (< 7 proteins, n = 52), which we called the X_L/X_O ratio (red). Both categories have been defined from results presented in Fig. 1B. The ratio of the median of autosomal gene expression of large complexes (n = 696) and the median of autosomal gene expression of other protein complexes (n = 151)—the A_L/A_O ratio (blue)—was computed similarly. Error bars have been obtained by bootstrapping protein complexes and computing both ratios and represent 95% bootstrap confidence interval. We pooled the data for eight tissues (see text) and computed the median and confidence interval the same way. The two green dashed lines indicate expectations with a twofold increase of expression (ratio of 2) and without any change in expression (ratio of 1).