Melissa A. Wilson Sayres

School of Life Sciences, Center for Evolution and Medicine

Arizona State University

 

There is tremendous sexual dimorphism in human genetic disease susceptibility, progression, and drug response. It is thus alarming that most genome-wide association studies exclude the most sexually dimorphic regions of our genome, the sex chromosomes. An essential component of incorporating the X and Y into studies of human disease, with their unique inheritance patterns, and response to population history and selection, is to understand their evolutionary history. Ancestrally, both the X and Y chromosomes shared identical gene content, but throughout our evolutionary history the Y chromosome has lost over 90% of the gene content it once shared with the X. The loss of Y-linked sequence not only affects the fate of the Y chromosome, but it also modulates the evolution and expression of X-linked genes. XX humans inactivate gene expression on one of their X chromosomes, but not completely; 15% of genes escape X-inactivation, while another 10% escape X-inactivation in only a subset of individuals. Analyzing patterns of heterogeneous X-inactivation across individual cell lines, we show that genes on the X chromosome are silenced in response to gene loss on the Y. Variation in these patterns of silencing are important for understanding the etiology of, and variation in, X-linked diseases.