Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome

TLDR

X‑chromosome inactivation evolved as a dosage‑compensation mechanism to equalize X‑linked gene expression between sexes, yet evidence for a global twofold increase (Ohno’s hypothesis) remains contradictory, particularly for dosage‑sensitive genes. The study aims to determine how dosage‑sensitive genes contribute to X‑aneuploidy phenotypes such as Turner and Klinefelter syndromes. The authors integrated dosage‑sensitivity data with X‑CI status to generate a list of candidate genes underlying X‑aneuploidy syndromes. They found that dosage‑sensitive genes encoding large protein complexes exhibit X‑linked expression comparable to autosomal genes, supporting Ohno’s hypothesis and refining its model of X‑CI evolution.

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.