Impact of the X chromosome and sex on regulatory variation

Kimberly R. Kukurba, Princy Parsana, Brunilda Balliu, Kevin S. Smith, Zachary Zappala, David A. Knowles, Marie Julie Favé, Joe R. Davis, 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

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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. Improving our understanding of these differences offers to elucidate the molecular mechanisms underlying sex-specific traits and diseases. However, to date, most studies have either ignored the X Chromosome or had insufficient power to test for the sex-specific impact of genetic variation. By analyzing whole blood transcriptomes of 922 individuals, we have conducted the first large-scale, genome-wide analysis of the impact of both sex and genetic variation on patterns of gene expression, including comparison between the X Chromosome and autosomes. We identified a depletion of expression quantitative trait loci (eQTL) 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 chromatin accessibility data through ATAC-sequencing to connect sex-specific chromatin accessibility to sex-specific patterns of expression and regulatory variation. As sex-specific regulatory variants discovered in our study can inform sex differences in heritable disease prevalence, we integrated our data with genome-wide association study data for multiple immune traits identifying several traits with significant sex biases in genetic susceptibilities. Together, our study provides genome-wide insight into how genetic variation, the X Chromosome, and sex shape human gene regulation and disease.

Original languageEnglish (US)
Pages (from-to)768-777
Number of pages10
JournalGenome research
Issue number6
StatePublished - Jun 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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