Sex differences in the human transcriptome are widespread and tissue specific, and they contribute to complex traits. The role of sex in the human transcriptome In humans, the inheritance of the XX or XY set of sex chromosomes is responsible for most individuals developing into adults expressing male or female sex-specific traits. However, the degree to which sex-biased gene expression occurs in tissues, especially those that do not contribute to characteristic sexually dimorphic traits. is unknown. Oliva et al. examined Genotype-Tissue Expression (GTEx) project data and found that 37% of genes in at least one of the 44 tissues studied exhibit a tissue-specific, sex-biased gene expression. They also identified a sex-specific variation in cellular composition across tissues. Overall, the effects of sex on gene expression were small, but they were genome-wide and mostly mediated through transcription factor binding. With sex-biased gene expression associated with loci identified in genome-wide association studies, this study lays the groundwork for identifying the molecular basis of male- and female-based diseases. Science, this issue p. eaba3066 INTRODUCTION Many complex human phenotypes, including diseases, exhibit sex-differentiated characteristics. These sex differences have been variously attributed to hormones, sex chromosomes, genotype × sex effects, differences in behavior, and differences in environmental exposures; however, their mechanisms and underlying biology remain largely unknown. The Genotype-Tissue Expression (GTEx) project provides an opportunity to investigate the prevalence and genetic mechanisms of sex differences in the human transcriptome by surveying many tissues that have not previously been characterized in this manner. RATIONALE To characterize sex differences in the human transcriptome and its regulation, and to discover how sex and genetics interact to influence complex traits and disease, we generated a catalog of sex differences in gene expression and its genetic regulation across 44 human tissue sources surveyed by the GTEx project (v8 data release), analyzing 16,245 RNA-sequencing samples and genotypes of 838 adult individuals. We report sex differences in gene expression levels, tissue cell type composition, and cis expression quantitative trait loci (cis-eQTLs). To assess their impact, we integrated these results with gene function, transcription factor binding annotation, and genome-wide association study (GWAS) summary statistics of 87 GWASs. RESULTS Sex effects on gene expression are ubiquitous (13,294 sex-biased genes across all tissues). However, these effects are small and largely tissue-specific. Genes with sex-differentiated expression are not primarily driven by tissue-specific gene expression and are involved in a diverse set of biological functions, such as drug and hormone response, embryonic development and tissue morphogenesis, fertilization, sexual reproduction and spermatogenesis, fat metabolism, cancer, and immune response. Whereas X-linked genes with higher expression in females suggest candidates for escape from X-chromosome inactivation, sex-biased expression of autosomal genes suggests hormone-related transcription factor regulation and a role for additional transcription factors, as well as sex-differentiated distribution of epigenetic marks, particularly histone H3 Lys27 trimethylation (H3K27me3). Sex differences in the genetic regulation of gene expression are much less common (369 sex-biased eQTLs across all tissues) and are highly tissue-specific. We identified 58 gene-trait associations driven by genetic regulation of gene expression in a single sex. These include loci where sex-differentiated cell type abundances mediate genotype-phenotype associations, as well as loci where sex may play a more direct role in the underlying molecular mechanism of the association. For example, we identified a female-specific eQTL in liver for the hexokinase HKDC1 that influences glucose metabolism in pregnant females, which is subsequently reflected in the birth weight of the offspring. CONCLUSION By integrating sex-aware analyses of GTEx data with gene function and transcription factor binding annotations, we describe tissue-specific and tissue-shared drivers and mechanisms contributing to sex differences in the human transcriptome and eQTLs. We discovered multiple sex-differentiated genetic effects on gene expression that colocalize with complex trait genetic associations, thereby facilitating the mechanistic interpretation of GWAS signals. Because the causative tissue is unknown for many phenotypes, analysis of the diverse GTEx tissue collection can serve as a powerful resource for investigations into the basis of sex-biased traits. This work provides an extensive characterization of sex differences in the human transcriptome and its genetic regulation. Sex affects gene expression and its genetic regulation across tissues. Sex effects on gene expression were measured in 44 GTEx human tissue sources and integrated with genotypes of 838 subjects. Sex-biased expression is present in numerous biological pathways and is associated to sex-differentiated transcriptional regulation. Sex-biased expression quantitative trait loci in cis (sex-biased eQTLs) are partially mediated by cellular abundances and reveal gene-trait associations. TT, AT, and AA are genotypes for a single-nucleotide polymorphism; TF, transcription factor. Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

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性别对人体组织基因表达的影响

人类转录组中的性别差异广泛存在且具有组织特异性，它们促成了复杂的性状。性别在人类转录组中的作用 在人类中，XX 或 XY 组性染色体的遗传是大多数个体发育成表达男性或女性性别特异性特征的成年人的原因。然而，性别偏见基因表达在组织中发生的程度，特别是那些对特征性二态性状没有贡献的组织。是未知的。奥利瓦等人。检查了基因型组织表达 (GTEx) 项目数据，发现所研究的 44 个组织中至少有一个组织中 37% 的基因表现出组织特异性、性别偏见的基因表达。他们还确定了跨组织细胞组成的性别特异性变化。总体而言，性别对基因表达的影响很小，但它们是全基因组的，主要通过转录因子结合介导。通过在全基因组关联研究中发现与基因座相关的性别偏见基因表达，本研究为确定男性和女性疾病的分子基础奠定了基础。科学，本期第 3 页。eaba3066 引言 许多复杂的人类表型，包括疾病，都表现出性别分化特征。这些性别差异被各种归因于激素、性染色体、基因型×性别效应、行为差异和环境暴露差异；然而，它们的机制和潜在的生物学在很大程度上仍然未知。基因型-组织表达 (GTEx) 项目提供了一个机会，通过调查许多以前没有以这种方式表征的组织来研究人类转录组中性别差异的普遍性和遗传机制。基本原理 为了表征人类转录组的性别差异及其调控，并发现性别和遗传如何相互作用以影响复杂的性状和疾病，我们在 44 个人类组织来源调查的基因表达及其遗传调控中生成了性别差异目录。 GTEx 项目（v8 数据发布），分析了 838 个成年人的 16,245 个 RNA 测序样本和基因型。我们报告了基因表达水平、组织细胞类型组成和顺式表达数量性状基因座 (cis-eQTL) 的性别差异。为了评估它们的影响，我们将这些结果与 87 个 GWAS 的基因功能、转录因子结合注释和全基因组关联研究 (GWAS) 汇总统计数据相结合。结果 性别对基因表达的影响无处不在（所有组织中有 13,294 个性别偏见基因）。然而，这些影响很小并且很大程度上是组织特异性的。具有性别差异表达的基因主要不是由组织特异性基因表达驱动，而是涉及多种生物学功能，例如药物和激素反应、胚胎发育和组织形态发生、受精、有性生殖和精子发生、脂肪代谢、癌症和免疫反应。而在雌性中具有较高表达的 X 连锁基因表明可以逃避 X 染色体失活，常染色体基因的性别偏见表达表明激素相关的转录因子调节和其他转录因子的作用，以及表观遗传标记的性别分化分布，特别是组蛋白 H3 Lys27 三甲基化 (H3K27me3)。基因表达的遗传调控中的性别差异不太常见（所有组织中有 369 个性别偏向的 eQTL），并且具有高度的组织特异性。我们确定了由单一性别中基因表达的遗传调控驱动的 58 个基因-性状关联。这些包括性别分化细胞类型丰度介导基因型-表型关联的基因座，以及性别可能在关联的潜在分子机制中发挥更直接作用的基因座。例如，我们在肝脏中发现了一个雌性特异性 eQTL，用于己糖激酶 HKDC1，它影响怀孕雌性的葡萄糖代谢，随后反映在后代的出生体重中。结论 通过将 GTEx 数据的性别感知分析与基因功能和转录因子结合注释相结合，我们描述了导致人类转录组和 eQTL 性别差异的组织特异性和组织共享驱动因素和机制。我们发现了多种性别差异遗传对基因表达的影响，这些影响与复杂的性状遗传关联共存，从而促进了 GWAS 信号的机械解释。由于许多表型的致病组织是未知的，因此对不同 GTEx 组织集合的分析可以作为研究性别偏见性状基础的强大资源。这项工作提供了人类转录组性别差异及其遗传调控的广泛表征。性别影响基因表达及其跨组织的遗传调控。在 44 个 GTEx 人体组织来源中测量了性别对基因表达的影响，并与 838 名受试者的基因型相结合。性别偏见表达存在于许多生物学途径中，并且与性别分化的转录调控有关。顺式中的性别偏向表达数量性状基因座（性别偏向的eQTL）部分由细胞丰度介导并揭示基因-性状关联。TT、AT 和 AA 是单核苷酸多态性的基因型；TF，转录因子。许多复杂的人类表型表现出性别分化特征。然而，这些差异背后的分子机制仍然很大程度上未知。我们在基因型-组织表达项目（GTEx，v8 版本）调查的 44 个人体组织来源中生成了基因表达和基因表达遗传调控的性别差异目录。我们证明了性别会影响整个人体组织样本的基因表达水平和细胞组成。总共 37% 的基因在至少一个组织中表现出性别偏见的表达。我们确定了具有性别差异效应的 cis 表达数量性状基因座 (eQTL) 并表征了它们的细胞起源。通过将有性别偏见的 eQTL 与全基因组关联研究数据相结合，我们确定了 58 个基因-性状关联，这些关联是由单一性别中基因表达的遗传调控驱动的。