Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving

Mol Biol Evol. 2013 Dec;30(12):2588-601. doi: 10.1093/molbev/mst148. Epub 2013 Sep 10.


In female mammals most X-linked genes are subject to X-inactivation. However, in humans some X-linked genes escape silencing, these escapees being candidates for the phenotypic aberrations seen in polyX karyotypes. These escape genes have been reported to be under stronger purifying selection than other X-linked genes. Although it is known that escape from X-inactivation is much more common in humans than in mice, systematic assays of escape in humans have to date employed only interspecies somatic cell hybrids. Here we provide the first systematic next-generation sequencing analysis of escape in a human cell line. We analyzed RNA and genotype sequencing data obtained from B lymphocyte cell lines derived from Europeans (CEU) and Yorubans (YRI). By replicated detection of heterozygosis in the transcriptome, we identified 114 escaping genes, including 76 not previously known to be escapees. The newly described escape genes cluster on the X chromosome in the same chromosomal regions as the previously known escapees. There is an excess of escaping genes associated with mental retardation, consistent with this being a common phenotype of polyX phenotypes. We find both differences between populations and between individuals in the propensity to escape. Indeed, we provide the first evidence for there being both hyper- and hypo-escapee females in the human population, consistent with the highly variable phenotypic presentation of polyX karyotypes. Considering also prior data, we reclassify genes as being always, never, and sometimes escape genes. We fail to replicate the prior claim that genes that escape X-inactivation are under stronger purifying selection than others.

Keywords: X-inactivation; expression evolution; rate of evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asian Continental Ancestry Group / genetics
  • Cell Line
  • European Continental Ancestry Group / genetics
  • Evolution, Molecular
  • Female
  • Gene Expression*
  • Genes, X-Linked*
  • Genetic Variation
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Mice
  • Mutation Rate
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, RNA
  • X Chromosome
  • X Chromosome Inactivation*