How differences in male vs. female gene expression drive infertility and disease
Men and women have almost identical genomes. Why then, do men and women have distinct, sex-specific susceptibilities to disease? A new study by Prof. Shmuel Pietrokovski and Dr. Moran Gershoni of the Department of Molecular Genetics has provided a comprehensive answer to this question, by revealing, for the first time, the way 6,500 genes (a third of all protein-coding genes in humans) are expressed differently in men and women.
As evidenced by differences in the male- and female-specific gene expression profiles—both in reproductive organs, and in tissues common to both sexes—the new study in BMC Biology helps explain why some diseases are more prevalent in one gender or another. It also sheds light on the genetic basis of a problem that men and women face together: the high incidence of human infertility.
An inherent bias
Gene expression is the process by which genetic instructions are transcribed and translated from our DNA. Prof. Pietrokovski and Dr. Gershoni analyzed data from the GTEx project—a study of human gene expression recorded for numerous organs and tissues from close to 550 adult participants. Looking closely at about 20,000 protein-coding genes, sorting them by the participants’ sex, and searching for differences in tissue-specific gene expression, the researchers found 6,500 genes with activity that was biased toward one sex or the other in at least one tissue.
This data-driven, computational biology approach yielded several discoveries that help explain the many well-known physiological differences between men and women. For example, genes found to be highly expressed in the skin of men or women are probably involved in the different growth of male and female body hair.
Sex-specific patterns of health and disease may also be traced to preferential gene expression in either men or women. To give just two examples, genes expressed only in the left ventricle of the female heart might play a role in sex-dependent patterns of cardiovascular diseases. Another gene found to have specific expression in older women is thought to explain the difference in the age at which men and women tend to experience the onset of Parkinson’s disease.
The scientists also found dozens of genes that have sex-dependent expression in several brain tissues. “While every individual is different, these clearly dissimilar patterns of gene expression might be related to differences in men’s and women’s patterns of behavior,” Prof. Pietrokovski says.
The infertility connection
The scientists also discovered that the more a gene was biased toward gene expression in one sex, the more likely it would be for that gene to appear in a mutated, and dysfunctional form. Moreover, they found a higher level of tolerance for such mutations in men—a finding with implications for infertility.
“Common sense says that these mutations, which directly reduce the number of offspring that carry them, should have been quickly weeded out by natural selection,” says Prof. Pietrokovski. “But mutations that only affect men—for example, those that cause sperm abnormality and sterility—can persist. This is because, while such mutations affect men only, they are passed down by women to their children, producing sons who are sterile, and daughters who continue to carry the mutated gene through the generations. This scenario may explain the relatively high incidence of detrimental mutations in genes specific to male or female reproductive tissues—mutations that remain a persistent part of our genetic inheritance, thus contributing to high levels of human infertility.”
According to Prof. Pietrokovski and Dr. Gershoni, the different ways in which genes are expressed—and the different ways in which traits driven by sex-preferential genetic bias are passed down through the generations—indicate that medical treatments for diseases, including infertility, should be designed with these differences in mind.
“From the vantage point of genetics, men and women undergo different selection pressures and therefore, at least to some extent, human evolution should be viewed as co-evolution. But our study also emphasizes the need for a better understanding of the differences between men and women in terms of the genes that cause disease, and which may affect the way men and women respond to treatment.”
Prof. Shmuel Pietrokovski’s research is supported by the Leo and Julia Forchheimer Center for Molecular Genetics; and the estate of Georges Lustgarten. Prof. Shmuel Pietrokovski is the incumbent of the Herman and Lilly Schilling Foundation Professorial Chair.