Impact of the X Chromosome and sex on regulatory variation
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 21, 2016
- Source ID
- 10.1101/gr.197897.115
Entities
People
- Alexis Battle
- Anshul Kundaje
- Brunilda Balliu
- David A. Knowles
- Douglas F. Levinson
- James B. Potash
- Jianxin Shi
- Joe R. Davis
- Kimberly R. Kukurba
- Marie-julie Favé
- Myrna M. Weissman
- Philip Awadalla
- Princy Parsana
- Sara Mostafavi
- Scott Smith
- Stephen B. Montgomery
- Xiaowei Zhu
- Xin Li
- Zachary Zappala
Organizations
- Air Force Office of Scientific Research
- Edward Mallinckrodt Jr. Foundation
- National Human Genome Research Institute
- National Institutes of Health
- Office of the Director
- United States Department of Defense