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Impact of the X chromosome and sex on regulatory variation

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
doi: https://doi.org/10.1101/024117
Kimberly R. Kukurba
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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Princy Parsana
3Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
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Kevin S. Smith
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
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Zachary Zappala
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
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David A. Knowles
3Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
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Marie-Julie Favé
5Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, QC, Canada
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Xin Li
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
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Xiaowei Zhu
6Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA
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James B. Potash
7Department of Psychiatry, University of Iowa Hospitals & Clinics, Iowa City, IA, USA
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Myrna M. Weissman
8Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, USA
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Jianxin Shi
9Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
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Anshul Kundaje
2Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
4Department of Computer Science, Stanford University, Stanford, CA, USA
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Douglas F. Levinson
6Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA
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Philip Awadalla
5Sainte-Justine University Hospital Research Centre, Department of Pediatrics, University of Montreal, Montreal, QC, Canada
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Sara Mostafavi
10Department of Statistics, University of British Columbia, Vancouver, BC, Canada
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Alexis Battle
3Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA
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  • For correspondence: ajbattle@cs.jhu.edu smontgom@stanford.edu
Stephen B. Montgomery
1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
2Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
4Department of Computer Science, Stanford University, Stanford, CA, USA
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  • For correspondence: ajbattle@cs.jhu.edu smontgom@stanford.edu
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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. 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 07, 2015.
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Impact of the X chromosome and sex on regulatory variation
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
bioRxiv 024117; doi: https://doi.org/10.1101/024117
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Impact of the X chromosome and sex on regulatory variation
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
bioRxiv 024117; doi: https://doi.org/10.1101/024117

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