Gene Expression Suggests Sexes Evolve Differently

A team of molecular geneticists has found that a large number of genes are expressed differently in men and women, which begins to explain why that despite sharing almost identical genomes the two sexes are distinctly dimorphic, with dissimilar disease susceptibilities and mutation rates.

To perform this study, investigators at the Weizmann Institute of Science called upon the resources of the Genotype-Tissue Expression project. The GTEx project was designed to provide to the scientific community a resource with which to study human gene expression and regulation and its relationship to genetic variation. This project collects and analyzes multiple human tissues from donors who are also densely genotyped, to assess genetic variation within their genomes. By analyzing global RNA expression within individual tissues and treating the expression levels of genes as quantitative traits, variations in gene expression that are highly correlated with genetic variation. Correlations between genotype and tissue-specific gene expression levels will help identify regions of the genome that influence whether and how much a gene is expressed. GTEx will help researchers to understand inherited susceptibility to disease and will be a resource database and tissue bank for many studies in the future.

Using information made available by the GTEx project, the Weizmann Institute investigators comprehensively mapped human sex-differential genetic architecture across 53 tissues. By analyzing GTEx RNA-sequencing data from 544 adults, they identified approximately 6,500 genes that were differentially expressed in the reproductive tracts and tissues common to both sexes.

The investigators reported in reported in the February 7, 2017, online edition of the journal BMC Biology that sex-differential genes were related to various biological systems, which suggested new insights into the pathophysiology of diverse human diseases. They 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. Many of the sex-specific genes that also underwent reduced selection efficiency were essential for successful reproduction in men or women. This seeming paradox might partially explain the high incidence of human infertility.

"In many species, females can produce only a limited number of offspring while males can, theoretically, father many more; so the species' survival will depend on more viable females in the population than males," said senior author Dr. Shmuel Pietrokovski, professor of molecular genetics at the Weizmann Institute of Science. "Thus natural selection can be more "lax" with the genes that are only harmful to males. Paradoxically, sex-linked genes are those in which harmful mutations are more likely to be passed down, including those that impair fertility. From this vantage point, men and women undergo different selection pressures and, at least to some extent, human evolution should be viewed as co-evolution. But the study also emphasizes the need for a better understanding of the differences between men and women in the genes that cause disease or respond to treatments."