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. 2024 Jul 25;25(5):bbae451.
doi: 10.1093/bib/bbae451.

Analysis of sex-biased gene expression in a Eurasian admixed population

Shuangshuang Cheng  1 , Zhilin Ning  2 , Ke Huang  2   3 , Yuan Yuan  2 , Xinjiang Tan  2 , Yuwen Pan  2 , Rui Zhang  2 , Lei Tian  2 , Yan Lu  1 , Xiaoji Wang  2 , Dongsheng Lu  2 , Yajun Yang  1 , Yaqun Guan  4 , Dolikun Mamatyusupu  5 , Shuhua Xu  1   2   3   6
Affiliations

Analysis of sex-biased gene expression in a Eurasian admixed population

Shuangshuang Cheng et al. Brief Bioinform. .

Abstract

Sex-biased gene expression differs across human populations; however, the underlying genetic basis and molecular mechanisms remain largely unknown. Here, we explore the influence of ancestry on sex differences in the human transcriptome and its genetic effects on a Eurasian admixed population: Uyghurs living in Xinjiang (XJU), by analyzing whole-genome sequencing data and transcriptome data of 90 XJU and 40 unrelated Han Chinese individuals. We identified 302 sex-biased expressed genes and 174 sex-biased cis-expression quantitative loci (sb-cis-eQTLs) in XJU, which were enriched in innate immune-related functions, indicating sex differences in immunity. Notably, approximately one-quarter of the sb-cis-eQTLs showed a strong correlation with ancestry composition; i.e. populations of similar ancestry tended to show similar patterns of sex-biased gene expression. Our analysis further suggested that genetic admixture induced a moderate degree of sex-biased gene expression. Interestingly, analysis of chromosome interactions revealed that the X chromosome acted on autosomal immunity-associated genes, partially explaining the sex-biased phenotypic differences. Our work extends the knowledge of sex-biased gene expression from the perspective of genetic admixture and bridges the gap in the exploration of sex-biased phenotypes shaped by autosome and X-chromosome interactions. Notably, we demonstrated that sex chromosomes cannot fully explain sex differentiation in immune-related phenotypes.

Keywords: Xinjiang’s Uyghurs; genetic admixture; local ancestry inference; sex-biased genes.

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Figures

Figure 1
Figure 1
SBGs in XJU and SBG comparison between XJU and ancestral source populations. (a) Volcano plot of SBGs in XJU. The x-axis indicates the degree of sex-biased gene expression estimated with log(M/F). The y-axis indicates the log10 transformed P-value of the significant sex-biased genes. Each dot indicates one gene. The red color indicates XJU FGs; the blue color indicates XJU MGs; the circles denote genes on autosomes; and the triangles denote genes on chromosome X. (b) Distribution of XJU SBGs across genomes. (c) Number of respective and overlapping SBGs in the XJU, EAS, and EUR populations.
Figure 2
Figure 2
Genetic regulation of sex-biased genes in XJU. (a) GWAS colocalization of the sb-cis-eQTL rs742108 and SLE loci. The left half of the figure shows the scatter plot of the P-value of the sb-cis-eQTLs and the SLE-associated GWAS loci, with different colors representing different LD strengths. The right half of the figure shows rs742108 as the most significant point (PP4 = 0.927). (b) This site is located within a 381 bp DNase cluster region with binding motifs for AR and ESR. According to the ENCODE annotation (GRCH37), rs742108 is located at the TF-binding site in the promoter near the PRDM1 gene. The red bar represents the TF-binding site; the light green bar represents the CTCF binding region; and the pink bar represents the gene promoter region. (c) The sex-biased association between rs742108 and PRDM1 and a schematic diagram of putative mechanisms associated with sex. In males and females, the different genotypes of rs742108 might lead to differential binding of the transcription complex with sex-biased TFs on the promoter, which results in different regulatory effects of the same variant in males and females. (d) Sex-biased association of rs118073539 and rs17237074 with OR56B4. The number in brackets above each boxplot indicates the sample size of each group.
Figure 3
Figure 3
Sex-biased gene expression differentiation. (a) Two admixture-induced sex-biased regulatory effects: induced alleles had similar or opposite regulatory effects on sex. (b) Schematic diagram of the ancestral-related subgroup identification at XJU. (c) The number of sex-biased DEGs between the eastern-derived and western-derived groups. The x-axis indicates the ANOVA P-value thresholds, and the y-axis indicates the differential gene numbers. (d) The number of sex-biased DEGs between the eastern-derived group and the EAS group, and between the western-derived group and the EAS group. The x-axis indicates the ANOVA P-value thresholds, which test the differential degree of the sex-biased gene expression, and the y-axis indicates the differential gene numbers. To control for the sample size in each group and each EAS cohort, we conducted a random sampling of the genes 30 times. A comparison of the differential gene numbers between the two groups was conducted with a t-test. **** indicates the highest significance.
Figure 4
Figure 4
Modeling of admixture-induced sex-biased gene expression. (a) Schematic diagram of admixture-induced sex-biased gene expression. (b) Example of sex-biased expression in three ancestral related subgroups of XJU. The degree of sex-biased expression was measured as log(F/M). (c) Verification of the model in XJU. (d) GWAS enrichments of ancestry-related sex-biased genes.
Figure 5
Figure 5
Sex-biased interactive regulatory effects between autosomes and X chromosomes in XJU. (a) Distal regulation of sex-biased gene expression between autosomes and X chromosomes. The genes in purple are located on the X chromosomes, and the genes in yellow are on the autosomes. (b) Schematic modeling of the mutual sex-biased gene expression regulation of autosomes and X chromosomes. (c) Schematic representation of MR to estimate the causal effect of BEX1 sex bias expression on AD prevalence using multiple instrumental variables (SNPs). (d) Flowchart of the interaction between autosomal sb-trans-eQTLs and the BEX1 gene on the X chromosomes affecting the incidence of AD in males and females in XJU (created with BioRender.com).
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