Kimberly R Kukurba, Princy Parsana, Kevin S Smith, Zachary Zappala, David A Knowles, Marie-Julie Favé, Xin Li, Xiaowei Zhu, James B Potash, Myrna M Weissman, Jianxin Shi, Anshul Kundaje, Douglas F Levinson, Philip Awadalla, Sara Mostafavi, Alexis Battle, Stephen B Montgomery
The X chromosome, with its unique mode of inheritance, contributes to differences between the sexes at a molecular level, including sex-specific gene expression and sex-specific impact of genetic variation. We have conducted an analysis of the impact of both sex and the X chromosome on patterns of gene expression identified through transcriptome sequencing of whole blood from 922 individuals. We identified that genes on the X chromosome are more likely to have sex-specific expression compared to the autosomal genes. Furthermore, we identified a depletion of regulatory variants on the X chromosome, especially among genes under high selective constraint. In contrast, we discovered an enrichment of sex-specific regulatory variants on the X chromosome. To resolve the molecular mechanisms underlying such effects, we generated and connected sex-specific chromatin accessibility to sex-specific expression and regulatory variation. As sex-specific regulatory variants can inform sex differences in genetic disease prevalence, we have integrated our data with genome-wide association study data for multiple immune traits and to identify traits with significant sex biases. Together, our study provides genome-wide insight into how the X chromosome and sex shape human gene regulation and disease.