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.Y degeneration | sex-linked gene expression | balance hypothesis

Expression reduction in mammalian X chromosome evolution refutes Ohno’s hypothesis of dosage compensation

“…6). Thus, our result is generally consistent with the suggestion of up-regulation of X-linked genes encoding components of large protein complexes (27). Nonetheless, these genes constitute only ∼5% of all X-linked genes, explaining why there is no chromosome-wide signal of X-up-regulation.…”

“…It was recently reported that human genes encoding components of large protein complexes (≥7 proteins) have a median X:AA expression ratio of ∼1, whereas the corresponding ratio for small protein complexes is ∼0.5 (27). Because dosage balance among components of large protein complexes is believed to be critical to the functionality of these complexes (28,29), this observation suggests that up-regulation may have occurred to those X-linked genes whose dosages are particularly important.…”

“…Whether the up-regulation of ∼5% of X-linked genes was sufficient to drive the origin of the chromosome-wide X inactivation in female mammals (27) is an open question. Outside mammals, sex chromosomes have evolved independently many times, but chromosome-wide dosage compensation between sexes is not universal (8,32).…”

Battle of the sexes: Conflict over dosage-sensitive genes and the origin of X chromosome inactivation

“…Female placental and marsupial mammals inactivate one of their two X chromosomes, effectively silencing gene expression from the inactive X and seemingly putting themselves at the same disadvantage as their brothers. In PNAS, Pessia et al (1) show that female X chromosome inactivation (XCI) is not in fact an act of solidarity by females but rather a result of the evolutionary tug of war over gene expression and sex chromosome dosage compensation that occurs between the sexes on the X chromosome.…”

“…This range suggests that selection for dosage compensation varies greatly across loci on the sex chromosomes. By choosing a subset of mammalian genes known to be dosage-sensitive (2, 12), Pessia et al (1) exploit this variance to test the requirements of Ohno's hypothesis. They find that dosage-sensitive X-linked genes are indeed expressed in both sexes at similar levels to loci on the autosomes.…”