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Sex Affects Gene Expression in Mammals

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Credit: Conor Gearin/Whitehead Institute.
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Men are from Mars and women are from Venus, so the saying goes. The differences between the sexes have been explored across a variety of disciplines over many years: philosophy, literature and, of course, science. From a biological perspective, however, the effect that sex has on gene expression, particularly in autosomal (sex-linked) genes, has been a relatively unmapped area – until now.

In their latest study published in Science, Professor of biology at the Massachusetts Institute of Technology (MIT) David Page and colleagues including Sahin Naqvi (former MIT graduate student and now postdoctoral researcher at Stanford University) report the discovery of genome-wide variations in gene expression between mammalian females and males.

Why were the researchers inspired to explore sex differences in gene expression? "We were motivated by the numerous diseases and traits that show differences between the sexes," Naqvi tells us – the most obvious trait being that males are generally taller than females. "In terms of disease, autoimmune disorders such as lupus and multiple sclerosis are more common in females, while autism and cardiovascular-related diseases are more common in males," Naqvi adds, "Despite this, we knew very little about molecular differences, such as gene expression levels, between the sexes in a range of different tissues and species." 

In their research, Naqvi et al. collected samples from 12 tissues in four non-human mammals (macaque, mouse, rat and dog), and then subjected the tissues to RNA sequencing. The tissues represented each germ layer (layers of cells that give rise to all of an organism's tissues and organs) in addition to the most major organ systems. "RNA sequencing allows one to measure expression levels of all genes in the genome," Naqvi comments. The scientists then analyzed this data with a large dataset of RNA sequencing from male and female human tissues, previously generated by the Genotype Tissue Expression Consortium (GTEx)

When asked the reason behind their choice of species for analysis, Naqvi tells us: "They represent common laboratory models, both in basic and pharmaceutical research. Evolutionarily speaking, these four species, when combined with humans, span a large fraction of the mammalian evolutionary tree, sharing a common ancestor ~100 million years ago." This enabled the researchers to infer approximately when in mammalian evolution certain sex biases in expression arose. 

Novel insight into molecular origins and evolution of sexual dimorphism

The study led to the discovery that a combination of sex biased genes accounts for approximately ~12% of the average height difference between men and women: "The conserved sex bias of genes that control human height allowed us to explain ~12% of the sex difference in human height. We believe this finding is significant because it serves as a proof-of-concept that sex biases in expression of genes otherwise operating equivalently in females and males can contribute to sex differences in traits," Naqvi tells us. 

The researchers' findings extend beyond height, however. Their data contains thousands of sex biased genes. Just less than a quarter of the sex biased genes catalogued appear to have evolved that sex bias in an early mammalian ancestor, and to have maintained the sex bias today in at least four of the five species that were studies. However, most of the genes appear to have evolved their sex bias more recently and are specific to either one species or a certain lineage, rodents or primates for example.

This specific finding warrants careful consideration of the use of non-human animal models in research that is translated to humans. Naqvi is quick to inform me that their work does not wholly discount the use of non-human models of sex differences, however: " Our finding that most sex bias in gene expression arose recently in mammalian evolution means that most sex bias in expression is specific to single species or subsets of species." Naqvi concludes: "This finding suggests that when using non-human models of sex difference, one should carefully consider, and perhaps determine empirically, whether the molecular sex differences observed recreate those in humans.

Reference: Conservation, acquisition, and functional impact of sex-biased gene expression in mammals. Science. July 19. Sahin Naqvi, Alexander K. Godfrey, Jennifer F. Hughes, Mary L. Goodheart, Richard N. Mitchell and David C. Page.