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 B, Weissman Myrna M, Shi Jianxin, Kundaje Anshul, Levinson Douglas F, Awadalla Philip, Mostafavi Sara, Battle Alexis, Montgomery Stephen B
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, Johns Hopkins University, Baltimore, Maryland 21218, USA;
Genome Res. 2016 Jun;26(6):768-77. doi: 10.1101/gr.197897.115. Epub 2016 Apr 21.
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.
X染色体具有独特的遗传模式，在分子水平上导致了两性之间的差异，包括性别特异性基因表达和遗传变异的性别特异性影响。增进我们对这些差异的理解有助于阐明性别特异性性状和疾病背后的分子机制。然而，迄今为止，大多数研究要么忽略了X染色体，要么没有足够的能力来检测遗传变异的性别特异性影响。通过分析922名个体的全血转录组，我们首次进行了大规模、全基因组范围的分析，研究性别和遗传变异对基因表达模式的影响，包括X染色体与常染色体之间的比较。我们发现X染色体上表达数量性状基因座（eQTL）减少，尤其是在受到高度选择约束的基因中。相比之下，我们发现X染色体上存在丰富的性别特异性调控变异。为了解析这些效应背后的分子机制，我们通过ATAC测序生成了染色质可及性数据，以将性别特异性染色质可及性与性别特异性表达和调控变异模式联系起来。由于我们研究中发现的性别特异性调控变异可以解释遗传性疾病患病率的性别差异，我们将我们的数据与多种免疫性状的全基因组关联研究数据相结合，确定了几种在遗传易感性方面存在显著性别偏差的性状。总之，我们的研究提供了全基因组范围的见解，以了解遗传变异、X染色体和性别如何塑造人类基因调控和疾病。
