Sex differences in interindividual gene expression variability across human tissues.
Sex differences in interindividual gene expression variability across human tissues.
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DOI：
10.1093/pnasnexus/pgac243
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发表时间：
2022-11
期刊：
影响因子：
--
通讯作者：
Zhao, Li
中科院分区：
文献类型：
--
作者：
Khodursky, Samuel;Jiang, Caroline S.;Zheng, Eric B.;Vaughan, Roger;Schrider, Daniel R.;Zhao, Li
从医学和进化的角度来看，理解表型性别差异一直是生物学的目标。虽然人们对性别间表型差异的研究很多，但对表型变异的性别差异却知之甚少。为了在分子水平上洞察个体间变异的性别差异，我们分析了来自基因类型-组织表达项目(GTEx)的43个组织的RNA-SEQ数据。在每个组织中，我们确定了在基因表达可变性方面表现出性别差异的基因。我们发现这些性别差异变量(SDV)基因与多种重要的生物学功能相关，包括性激素反应、免疫反应和其他信号通路。通过分析从乳腺上皮细胞中收集的单细胞RNA测序数据，我们发现在乳腺组织中基因表达变异性存在性别差异的基因倾向于以细胞类型特异性的方式表达。我们寻找SDV表达与Graves病之间的关联，Graves病是一种众所周知的严重偏向女性的疾病，我们发现在甲状腺组织中女性变异性较高的基因中，Graves相关基因显著丰富。这表明SDV的表达在性别偏见疾病中可能起到作用。然后，我们检查了作用于变异性性别差异基因的进化约束，发现它们显示出选择性约束增加的证据。通过对性别偏向eQTL数据的分析，我们发现了SDV表达可能有遗传基础的证据。最后，我们提出了一个简单的进化模型，用于从性别特定的限制中出现SDV表达。
Understanding phenotypic sex differences has long been a goal of biology from both a medical and evolutionary perspective. Although much attention has been paid to mean differences in phenotype between the sexes, little is known about sex differences in phenotypic variability. To gain insight into sex differences in interindividual variability at the molecular level, we analyzed RNA-seq data from 43 tissues from the Genotype-Tissue Expression project (GTEx). Within each tissue, we identified genes that show sex differences in gene expression variability. We found that these sex-differentially variable (SDV) genes are associated with various important biological functions, including sex hormone response, immune response, and other signaling pathways. By analyzing single-cell RNA sequencing data collected from breast epithelial cells, we found that genes with sex differences in gene expression variability in breast tissue tend to be expressed in a cell-type-specific manner. We looked for an association between SDV expression and Graves’ disease, a well-known heavily female-biased disease, and found a significant enrichment of Graves’ associated genes among genes with higher variability in females in thyroid tissue. This suggests a possible role for SDV expression in sex-biased disease. We then examined the evolutionary constraints acting on genes with sex differences in variability and found that they exhibit evidence of increased selective constraint. Through analysis of sex-biased eQTL data, we found evidence that SDV expression may have a genetic basis. Finally, we propose a simple evolutionary model for the emergence of SDV expression from sex-specific constraints.
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