Abstract

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.

中文翻译：

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常染色体性别相关的共甲基化区域通过 DNA 甲基化预测生物学性别

摘要

性是健康的调节剂，在生物医学研究中一直被忽视。认识到这一知识差距，资助机构现在要求将性作为一个生物学变量纳入其中，目的是激发人们努力阐明健康和疾病中性别偏见的分子基础。DNA甲基化（DNAm）是调解这种性别偏见的强有力的分子候选者；然而，尚未出现对 DNAm 中性别差异的有力且特征明确的注释。以大 ( n = 3795) 来自标准成人全血样本的 DNAm 谱数据集，我们识别、验证和表征了常染色体性相关的共甲基化基因组区域 (sCMR)。引人注目的是，sCMRs 在整个生命过程中显示出一致的 DNAm 性别差异，并且一个子集在细胞、组织和癌症类型中也是一致的。sCMR 包括已知 DNAm 性别差异的站点，以及与具有性别偏见影响的健康状况的联系。sCMR 的稳健性使得能够以 96% 的准确率生成基于常染色体 DNAm 的性别预测因子。对患有性染色体非整倍体（Klinefelter [47,XXY]、Turner [45,X] 和 47,XXX 综合征）的个体的血液 DNAm 谱进行测试，揭示了性染色体与性别偏向的常染色体 DNAm 之间的密切关系。