Autosomal sex-associated co-methylated regions predict biological sex from DNA methylation

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  • Evan Gatev, Bulgarian Academy of Sciences, University of British Columbia, Simon Fraser University
  • ,
  • Amy M. Inkster, University of British Columbia
  • ,
  • Gian Luca Negri, University of British Columbia
  • ,
  • Chaini Konwar, University of British Columbia
  • ,
  • Alexandre A. Lussier, Harvard University, Broad Institute
  • ,
  • Anne Skakkebaek
  • Marla B. Sokolowski, University of Toronto, CIFAR
  • ,
  • Claus H. Gravholt
  • Erin C. Dunn, Harvard University, Broad Institute
  • ,
  • Michael S. Kobor, University of British Columbia, CIFAR
  • ,
  • Maria J. Aristizabal, University of British Columbia, University of Toronto, CIFAR, Queen's University

Sex is a modulator of health that has been historically overlooked in biomedical research. Recognizing this knowledge gap, funding agencies now mandate the inclusion of sex as a biological variable with the goal of stimulating efforts to illuminate the molecular underpinnings of sex biases in health and disease. DNA methylation (DNAm) is a strong molecular candidate for mediating such sex biases; however, a robust and well characterized annotation of sex differences in DNAm is yet to emerge. Beginning with a large (n = 3795) dataset of DNAm profiles from normative adult whole blood samples, we identified, validated and characterized autosomal sex-associated co-methylated genomic regions (sCMRs). Strikingly, sCMRs showed consistent sex differences in DNAm over the life course and a subset were also consistent across cell, tissue and cancer types. sCMRs included sites with known sex differences in DNAm and links to health conditions with sex biased effects. The robustness of sCMRs enabled the generation of an autosomal DNAm-based predictor of sex with 96% accuracy. Testing this tool on blood DNAm profiles from individuals with sex chromosome aneuploidies (Klinefelter [47,XXY], Turner [45,X] and 47,XXX syndrome) revealed an intimate relationship between sex chromosomes and sex-biased autosomal DNAm.

TidsskriftNucleic Acids Research
Sider (fra-til)9097-9116
Antal sider20
StatusUdgivet - sep. 2021

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