Impact of the X chromosome and sex on regulatory variation

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

69 Scopus Citations
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  • Kimberly R. Kukurba
  • Princy Parsana
  • Brunilda Balliu
  • Kevin S. Smith
  • Zachary Zappala
  • David A. Knowles
  • Marie-Julie Favé
  • Joe R. Davis
  • Xin Li
  • James B. Potash
  • Myrna M. Weissman
  • Jianxin Shi
  • Anshul Kundaje
  • Douglas F. Levinson
  • Philip Awadalla
  • Sara Mostafavi
  • Alexis Battle
  • Stephen B. Montgomery


Original languageEnglish
Pages (from-to)768-777
Journal / PublicationGenome Research
Issue number6
Publication statusPublished - 1 Jun 2016
Externally publishedYes



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.

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Impact of the X chromosome and sex on regulatory variation. / Kukurba, Kimberly R.; Parsana, Princy; Balliu, Brunilda et al.
In: Genome Research, Vol. 26, No. 6, 01.06.2016, p. 768-777.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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