In many mammals, there are clear differences between the sexes. Average heights get higher in men relative to women, for example. There are also physiological differences between the sexes, some of which impact disease risk; women are at greater risk for autoimmune disorders, while men tend to have higher rates of cardiovascular disease. We still don’t know a lot about how gene expression in males and females differs, however. A new study aimed to reveal more about those genetic differences. This study, which was reported in Science, can help show how sex-biased changes in gene expression influence biology. Most rodent models used in research tend to be male, partly to eliminate the confounding influence of female hormonal cycles; this work can illuminate previously unknown implications of sex-bias in research.
To assess gene expression differences between the sexes, the researchers performed extensive RNA sequencing, which identifies the active genes in a tissue or organism. In this work, the scientists focused on twelve kinds of tissues in five organisms. They found that genes that are expressed differently in men and women account for about twelve percent of the height difference between the sexes.
“Discovering contributions of sex-biased gene expression to height is exciting because identifying the determinants of height is a classic, century-old problem, and yet by looking at sex differences in this new way we were able to provide new insights,” noted Whitehead Institute Director David Page. “My hope is that we and other researchers can repeat this model to similarly gain new insights into diseases that show sex bias."
Importantly, the scientists found that most gene expression changes between the sexes are not mirrored among species; sex-biased genes may be having a different impact on disease in humans than they do in research animals.
“We’re not saying to avoid animal models in sex differences research, only not to take for granted that the sex-biased gene expression behind a trait or disease observed in an animal will be the same as that in humans. Now that researchers have species and tissue-specific data available to them, we hope they will use it to inform their interpretation of results from animal models,” said study first author Sahin Naqvi, a former Massachusetts Institute of Technology (MIT) graduate student who is currently a postdoctoral researcher at Stanford University.
The team also investigated what is driving the differential expression in the sexes. Naqvi found evidence that transcription factors, which affect gene expression, are not the same in males and females. Some sex-biased genes have a transcription factor that behaves differently in the sexes in promotor regions, where genes can be activated. Male transcription factors will bind to the promotors of male-biased genes, and female transcription factors act similarly on female-biased genes. Sex chromosomes and hormones control the differences between the sexes, which may ultimately be influencing the transcription factors. More research will be needed to understand the process completely.
“We’re beginning to build the infrastructure for a systematic understanding of sex biases throughout the body,” added Page, who is also a professor of biology at MIT and a Howard Hughes Medical Institute investigator. “We hope these datasets are used for further research, and we hope this work gives people a greater appreciation of the need for, and value of, research into the molecular differences in male and female biology.”