Autosomal genetic control of human gene expression does not differ across the sexes

Kassam, Irfahan; Lloyd‐Jones, Luke R.; Holloway, Alexander; Small, Kerrin S.; Zeng, Biao; Bakshi, Andrew; Metspalu, Andres; Gibson, Greg; Spector, Tim D.; Esko, Tõnu; Montgomery, Grant W.; Powell, Joseph E.; Yang, Jian; Visscher, Peter M.; McRae, Allan F.

doi:10.1186/s13059-016-1111-0

Cited by 15 publications

(12 citation statements)

References 41 publications

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“…Many studies have aimed to identify sex-specific genetic control of autosomal gene expression (21)(22)(23)(24), however the evidence for differential genetic control of gene expression across the sexes is largely inconsistent. Indeed, our previous work has shown that, on average, males and females share a common autosomal genetic control of gene expression in whole blood (25). This is consistent with sex-differences in gene expression being due to differences in the regulatory genome across the sexes (10,11), and may be due to differential binding of sex hormones affecting the expression of nearby genes.…”

Section: Introductionsupporting

confidence: 68%

Tissue-specific sex differences in human gene expression

Kassam

Yang

et al. 2019

Human Molecular Genetics

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Despite extensive sex differences in human complex traits and disease, the male and female genomes differ only in the sex chromosomes. This implies that most sex-differentiated traits are the result of differences in the expression of genes that are common to both sexes. While sex differences in gene expression have been observed in a range of different tissues, the biological mechanisms for tissue-specific sex differences (TSSDs) in gene expression are not well understood. A total of 30 640 autosomal and 1021 X-linked transcripts were tested for heterogeneity in sex difference effect sizes in n = 617 individuals across 40 tissue types in Genotype–Tissue Expression (GTEx). This identified 65 autosomal and 66 X-linked TSSD transcripts (corresponding to unique genes) at a stringent significance threshold. Results for X-linked TSSD transcripts showed mainly concordant direction of sex differences across tissues and replicate previous findings. Autosomal TSSD transcripts had mainly discordant direction of sex differences across tissues. The top cis-expression quantitative trait loci (eQTLs) across tissues for autosomal TSSD transcripts are located a similar distance away from the nearest androgen and estrogen binding motifs and the nearest enhancer, as compared to cis-eQTLs for transcripts with stable sex differences in gene expression across tissue types. Enhancer regions that overlap top cis-eQTLs for TSSD transcripts, however, were found to be more dispersed across tissues. These observations suggest that androgen and estrogen regulatory elements in a cis region may play a common role in sex differences in gene expression, but TSSD in gene expression may additionally be due to causal variants located in tissue-specific enhancer regions.

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Section: Introductionsupporting

confidence: 68%

Tissue-specific sex differences in human gene expression

Kassam

Yang

et al. 2019

Human Molecular Genetics

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“…Kassam et al . examined the sex-specific genetic architecture of autosomal gene expression in whole blood samples from about one thousand men and one thousand women using DNA arrays [ 55 ]. No differences between men and women were found in autosomal genetic control of gene expression.…”

Section: Discussionmentioning

confidence: 99%

The landscape of sex-differential transcriptome and its consequent selection in human adults

2017

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BackgroundThe prevalence of several human morbid phenotypes is sometimes much higher than intuitively expected. This can directly arise from the presence of two sexes, male and female, in one species. Men and women have almost identical genomes but are distinctly dimorphic, with dissimilar disease susceptibilities. Sexually dimorphic traits mainly result from differential expression of genes present in both sexes. Such genes can be subject to different, and even opposing, selection constraints in the two sexes. This can impact human evolution by differential selection on mutations with dissimilar effects on the two sexes.ResultsWe comprehensively mapped human sex-differential genetic architecture across 53 tissues. Analyzing available RNA-sequencing data from 544 adults revealed thousands of genes differentially expressed in the reproductive tracts and tissues common to both sexes. Sex-differential genes are related to various biological systems, and suggest new insights into the pathophysiology of diverse human diseases. We also identified a significant association between sex-specific gene transcription and reduced selection efficiency and accumulation of deleterious mutations, which might affect the prevalence of different traits and diseases. Interestingly, many of the sex-specific genes that also undergo reduced selection efficiency are essential for successful reproduction in men or women. This seeming paradox might partially explain the high incidence of human infertility.ConclusionsThis work provides a comprehensive overview of the sex-differential transcriptome and its importance to human evolution and human physiology in health and in disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0352-z) contains supplementary material, which is available to authorized users.

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“…Differences between the sexes in complex traits could be partially explained by sex-specific gene expression regulation, which could lead to differences downstream across biological pathways and traits, and thus to the detection of GxS interactions in GWASs. Although studies have been carried out searching for differential gene expression between the sexes (sex-DE) in a variety of tissues of interest, studies linking sex to differences in gene expression regulation (sex-specific or sex-biased eQTLs) are few, with often contradictory results 5,[37][38][39][40] . These mixed results could be due to the contribution of GxS to gene expression being tissue specific, a lack of sufficient statistical power, or the fact that this contribution occurs only on a small number of genes .…”

Section: Sex Differences In Gene Expression Regulationmentioning

confidence: 99%

Sexual differences in genetic architecture in UK Biobank

Bernabeu¹,

Canela-Xandri²,

Rawlik³

et al. 2020

Preprint

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Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Gene by sex interactions (GxS) are thought to account for some of this sexual dimorphism. However, the extent and basis of these interactions are poorly understood.Here we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We also found that, in some cases, sex-agnostic GWAS efforts might be missing loci of interest, and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the dimorphism observed through sex-biased eQTL and gene-level analyses.This study marks a broad examination of the genetics of sexual dimorphism. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Our results suggest the need to consider sex-stratified analyses for future studies in order to shed light into possible sex-specific molecular mechanisms.

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Autosomal genetic control of human gene expression does not differ across the sexes

Cited by 15 publications

References 41 publications

Tissue-specific sex differences in human gene expression

Tissue-specific sex differences in human gene expression

The landscape of sex-differential transcriptome and its consequent selection in human adults

Sexual differences in genetic architecture in UK Biobank

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