Adrianna San Roman, PhD, Frontiers In Human Genetics Conference, October 10, 2024

Genomic Contributions to Sex Differences in Human Biology

ABSTRACT

Biomedical research has historically ignored the role that sex differences play in health and disease, resulting in disparities in both healthcare and our understanding of the basic human biology that drives medical advancements. However, there is an increasing appreciation for differences between sexes that manifest across the lifespan and in disease. The biological origins of these sex differences are poorly understood, even though sex chromosome constitution—the number of X and Y chromosomes—is the largest source of genetic variation in the human population. To understand the cellular impacts of this variation, we sampled blood and skin from individuals with a range of sex chromosome constitutions—from one to four copies of the X and zero to four copies of the Y. Quantitative analyses of gene expression across these cells identified X chromosome genes that may mediate phenotypic effects of X chromosome copy number and revealed a novel gene regulatory mechanism through which the inactive X modulates transcription from the active X. More broadly, we found that thousands of autosomal genes cell-autonomously respond to X and/or Y chromosome copy number, and that a pair of transcription factors on the sex chromosomes is a key driver of these gene expression programs. These results provide a foundation for future work to elucidate molecular mechanisms linking genomic and phenotypic sex differences in humans.