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Genome Res. 2016 Jun;26(6):768-77. doi: 10.1101/gr.197897.115. Epub 2016 Apr 21.

Impact of the X Chromosome and sex on regulatory variation.

Author information

1
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA;
2
Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA;
3
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
4
Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, Québec H3T 1J4, Canada;
5
Department of Psychiatry, Stanford University School of Medicine, Stanford, California 94305, USA;
6
Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, USA;
7
Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, New York 10032, USA;
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA;
9
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Computer Science, Stanford University, Stanford, California 94305, USA;
10
Department of Statistics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
11
Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA; ajbattle@cs.jhu.edu smontgom@stanford.edu.
12
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Computer Science, Stanford University, Stanford, California 94305, USA; ajbattle@cs.jhu.edu smontgom@stanford.edu.

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.

PMID:
27197214
PMCID:
PMC4889977
DOI:
10.1101/gr.197897.115
[Indexed for MEDLINE]
Free PMC Article

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