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An investigation of the genetic and epigenetic factors underlying escape from X-chromosome inactivation Balaton, Bradley

Abstract

X-chromosome inactivation (XCI) is the process by which one of the X chromosomes in XX females is silenced to express similar levels of X-linked genes with XY males. This silencing is incomplete as some genes escape from XCI and other genes vary their XCI status across populations, tissues or samples. Here I derive consensus XCI status calls in humans, extend XCI status calls across species, and determine the relationship between XCI status and various epigenetic marks. I aggregated XCI status calls from multiple studies, deriving XCI status calls for 639 human genes. I found 12% of genes escaping from XCI, 8% variably escaping XCI, and 7% discordant across studies. To make XCI status calls across species I obtained DNA methylation data for 12 species, allowing us to generate an average of 387 XCI calls per species. Overall, 12% of genes escaped XCI, with mouse an outlier with only 5%. Of the genes with predictions across at least four species, 74.8% of them were entirely consistent and only 6% had more than one inconsistent species. Many genes were seen to have primate-specific escape from XCI, while only one gene had an artiodactyla-specific XCI status. The consensus XCI status calls were compared to DNA methylation and commonly analyzed histone marks. I found the expected trend where repressive marks were enriched at genes subject to XCI and activating marks were enriched at genes escaping XCI; however, the histone marks had a large overlap between levels seen at genes subject to XCI and genes escaping from XCI. Only DNAme could accurately predict an individual gene’s XCI status. I combined the marks and found that we could make XCI status calls with 75% accuracy for genes escaping from XCI and 90% accuracy for genes subject to XCI. The marks with the greatest contribution to this predictor were DNAme, H3K27me3 and H3K4me3. The results of these projects further our understanding of which genes escape from XCI, which may be important for analysis of sexual dimorphism and further provide us a means to examine how silencing may be regulated in humans and across mammals.

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Attribution-NonCommercial-ShareAlike 4.0 International