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 Bennett Potash, Myrna M. Weissman, Jianxin Shi, Anshul Kundaje, Douglas F. Levinson, Philip Awadalla, Sara Mostafavi, Alexis Battle, Stephen B. Montgomery

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)768-777
Number of pages10
JournalGenome Research
Volume26
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

Fingerprint

X Chromosome
Sex Characteristics
Sex Chromatin
Genome
Gene Expression
Sexism
Quantitative Trait Loci
Genome-Wide Association Study
Genetic Predisposition to Disease
Transcriptome
Genes
Chromatin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Kukurba, K. R., Parsana, P., Balliu, B., Smith, K. S., Zappala, Z., Knowles, D. A., ... Montgomery, S. B. (2016). Impact of the X chromosome and sex on regulatory variation. Genome Research, 26(6), 768-777. https://doi.org/10.1101/gr.197897.115

Impact of the X chromosome and sex on regulatory variation. / Kukurba, Kimberly R.; Parsana, Princy; Balliu, Brunilda; Smith, Kevin S.; Zappala, Zachary; Knowles, David A.; Favé, Marie Julie; Davis, Joe R.; Li, Xin; Zhu, Xiaowei; Potash, James Bennett; Weissman, Myrna M.; Shi, Jianxin; Kundaje, Anshul; Levinson, Douglas F.; Awadalla, Philip; Mostafavi, Sara; Battle, Alexis; Montgomery, Stephen B.

In: Genome Research, Vol. 26, No. 6, 01.06.2016, p. 768-777.

Research output: Contribution to journalArticle

Kukurba, KR, Parsana, P, Balliu, B, Smith, KS, Zappala, Z, Knowles, DA, Favé, MJ, Davis, JR, Li, X, Zhu, X, Potash, JB, Weissman, MM, Shi, J, Kundaje, A, Levinson, DF, Awadalla, P, Mostafavi, S, Battle, A & Montgomery, SB 2016, 'Impact of the X chromosome and sex on regulatory variation', Genome Research, vol. 26, no. 6, pp. 768-777. https://doi.org/10.1101/gr.197897.115
Kukurba KR, Parsana P, Balliu B, Smith KS, Zappala Z, Knowles DA et al. Impact of the X chromosome and sex on regulatory variation. Genome Research. 2016 Jun 1;26(6):768-777. https://doi.org/10.1101/gr.197897.115
Kukurba, Kimberly R. ; Parsana, Princy ; Balliu, Brunilda ; Smith, Kevin S. ; Zappala, Zachary ; Knowles, David A. ; Favé, Marie Julie ; Davis, Joe R. ; Li, Xin ; Zhu, Xiaowei ; Potash, James Bennett ; Weissman, Myrna M. ; Shi, Jianxin ; Kundaje, Anshul ; Levinson, Douglas F. ; Awadalla, Philip ; Mostafavi, Sara ; Battle, Alexis ; Montgomery, Stephen B. / Impact of the X chromosome and sex on regulatory variation. In: Genome Research. 2016 ; Vol. 26, No. 6. pp. 768-777.
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