title: Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving.
abstract: 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.
authors.affiliation: State Key Laboratory of Medical Genomics, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Atahualpa
authors.initials: A
authors.lastname: Castillo-Morales
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhu
authors.forename: Landian
authors.initials: L
authors.lastname: Hu
authors.forename: Araxi O
authors.initials: AO
authors.lastname: Urrutia
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Kong
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Hurst
mesh_terms: D000818:Animals; D044466:Asian People / Q000235:genetics; D002460:Cell Line; D019143:Evolution, Molecular; D005260:Female; D015870:Gene Expression; D050172:Genes, X-Linked; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D059645:Mutation Rate; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017423:Sequence Analysis, RNA; D044465:White People / Q000235:genetics; D014960:X Chromosome; D049951:X Chromosome Inactivation
keywords: X-inactivation; expression evolution; rate of evolution
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