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The Landscape of Sex-Differential Transcriptome and Its Consequent Selection in Human Adults

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The Landscape of Sex-Differential Transcriptome and Its Consequent Selection in Human Adults

Moran Gershoni et al. BMC Biol.

Abstract

Background: The 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.

Results: We 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.

Conclusions: This work provides a comprehensive overview of the sex-differential transcriptome and its importance to human evolution and human physiology in health and in disease.

Keywords: Sex-differential expression; Sex-differential selection; Sexual dimorphism.

Figures

Fig. 1
Fig. 1
Box plot of (a) sex-differential expression (SDE) scores of all protein-coding genes, and (b) the number of SDE genes in 45 tissues common to men and women. Most genes are not differentially expressed, and have an SDE score of zero. Positive and negative values denote women- and men-biased expression, respectively, colored according to their organs or their biological-system affiliation
Fig. 2
Fig. 2
Heatmap of sex-differential expression (SDE) scores of all genes with at least one SDE in non-mammary gland tissue. Red denotes women specificity and blue denotes men specificity. The genes are grouped according to principal component analysis clusters (Additional file 8: Figure S6). Tissues are grouped using hierarchical clustering
Fig. 3
Fig. 3
Examples of various patterns of differential expression. Expression of genes TCHH, CPZ, PAGE4, MYH1, NPPB, and ZFX in 53 human tissues. Reads per kilobase of transcript per million values of these genes were retrieved from the GTEx project data [27, 28]. Red bars denote women samples and blue bars denote men samples; pink bars denote women reproductive tissues and light blue bars denote men reproductive tissues
Fig. 4
Fig. 4
Heatmap of sex-differential expression (SDE) scores of the sex-specific and moderately sex-specific genes, colored as in Fig. 2. Red, blue, and purple boxes denote major women, men, and combined gene clusters, respectively
Fig. 5
Fig. 5
Population genetics of selection pressures. Population distribution frequencies (y-axis) of protein-coding gene (a) dStop/dS and (b) dDNS/dS values in the 1000 Genome Project, Phase 3, for different minor allele frequency (MAF) ranges (x-axis). Different dStop/dS and dDNS/dS ratio ranges are denoted by different colors (see key). dDNS deleterious non-synonymous, dS deleterious synonymous, dSTOP deleterious stop-gain
Fig. 6
Fig. 6
Sex-specific expression and purifying selection. a dDNS/dS ratios of different groups of genes (Table 1, black bars) and the mean (white circles) and standard deviations (lines) of 10,000 random control sets with the corresponding number of genes. b Inverse correlation between sex specificity and selection efficiency. dDNS deleterious non-synonymous, dS deleterious synonymous

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