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

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

Yuchao Zhang et al. Mol Biol Evol. 2013 Dec.

Erratum in

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.

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

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Figures

F<sc>ig</sc>. 1.

Fig. 1.

The location of escape genes in CEU and YRI cluster in similar chromosomal locations. The genes found in more than three individuals and in greater than 50% of the potentially informative samples are considered to be common escape genes (red) in each population, whereas the others are rare escape genes (blue) in the populations. The genes solely replicated via more than one SNPs per gene are not included. Their inclusion makes no difference to qualitative trends. The x axis refers to the count of individuals with evidence for escape in the corresponding genes. Note Xist is within the Xic domain.

F<sc>ig</sc>. 2.

Fig. 2.

_K_a/_K_s ratios of genes in the three X-inactivation classes in the merged data set. P values indicate significance on pairwise Mann–Whitney U tests. There are 35 that always escape, 206 always inactivated, and 205 heterogeneous (N = 446). Evolutionary rates are from the human–macaque orthologous genes with numbers taken from Ensembl or from Park et al. (2010). Outliners are not shown. Transverse lines indicate the median value.

F<sc>ig</sc>. 3.

Fig. 3.

Location of escape genes and haploid expressed genes on the X chromosome of one individual of CEU (NA12004) and YRI (NA18511). Genes marked as a “potential site” are those where there is exonic heterozygozity at the DNA level and transcripts that pass the coverage threshold but that do not show evidence of escape (i.e., no evidence of biallelic expression). Those marked in blue/red show evidence of escape. The sum height of the colored bar indicates the net read depth summing over both alleles. The proportion of blue to red indicates the proportion of expression from the inactive X chromosome (blue) and the active X chromosome (we always presume the minority allele is from the inactive X chromosome). The data for the pattern of escape from the remaining individuals are shown in

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