Abstract
BackgroundSex is an important but understudied factor in the genetics of human diseases. Analyses using a combination of gene expression data, ENCODE data, and evolutionary data of sex-biased gene expression in human tissues can give insight into the regulatory and evolutionary forces acting on sex-biased genes.MethodsIn this study, we analyzed the differentially expressed genes between males and females. On the X chromosome, we used a novel method and investigated the status of genes that escape X-chromosome inactivation (escape genes), taking into account the clonality of lymphoblastoid cell lines (LCLs). To investigate the regulation of sex-biased differentially expressed genes (sDEG), we conducted pathway and transcription factor enrichment analyses on the sDEGs, as well as analyses on the genomic distribution of sDEGs. Evolutionary analyses were also conducted on both sDEGs and escape genes.ResultsGenome-wide, we characterized differential gene expression between sexes in 462 RNA-seq samples and identified 587 sex-biased genes, or 3.2% of the genes surveyed. On the X chromosome, sDEGs were distributed in evolutionary strata in a similar pattern as escape genes. We found a trend of negative correlation between the gene expression breadth and nonsynonymous over synonymous mutation (dN/dS) ratios, showing a possible pleiotropic constraint on evolution of genes. Genome-wide, nine transcription factors were found enriched in binding to the regions surrounding the transcription start sites of female-biased genes. Many pathways and protein domains were enriched in sex-biased genes, some of which hint at sex-biased physiological processes.ConclusionsThese findings lend insight into the regulatory and evolutionary forces shaping sex-biased gene expression and their involvement in the physiological and pathological processes in human health and diseases.
Highlights
Sex is an important but understudied factor in the genetics of human diseases
We investigate whether there are differences in replication timing in male- and female-biased genes, and whether specific regions of the chromosomes are enriched in sex-biased gene expression, both linearly along the chromosome and in the 3D topologically associated domains (TADs)
Expressed genes between sexes Using the package TweeDESeq and a Benjamini-Hochberg false discovery rate (FDR) cutoff of 0.05, we identified 587 genes genome-wide that are differentially expressed between males and females in the lymphoblastoid cell line (LCL), which accounted for 3.2% of the genes surveyed
Summary
Sex is an important but understudied factor in the genetics of human diseases. Analyses using a combination of gene expression data, ENCODE data, and evolutionary data of sex-biased gene expression in human tissues can give insight into the regulatory and evolutionary forces acting on sex-biased genes. Studies into the genes that have sex-biased gene expression, both on the autosomes and on the X chromosome, and into the regulatory and evolutionary forces that sculpt these genes to be sex biased will have implications for both evolutionary and medical genetics. Promoters and enhancers are further marked by the presence of specific histone modifications, such as H3K4me. All of histone modification marks [5], chromatin accessibility [6, 7], and replication timing [7] have been found to have sex-specific elements, leading to questions about what we can learn about gene regulation and evolution from these genomic features. We use a variety of genomic features and evolutionary measurements to investigate regulatory and evolutionary forces on sex-biased genes
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