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, we are developing an increasing appreciation for important differences between sexes that manifest across the lifespan and in disease. Sex-biased phenotypes can be found in physical traits such as height, body fat percentage, and proportions of immune cell types. Furthermore, a wide variety of diseases have significant sex-biases. For instance, many autoimmune diseases are more prevalent in females, including lupus, which occurs in nine females for every one male. In contrast, most non-reproductive cancers, and several neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder are more common in males. The molecular mechanisms that lead to these sex differences are largely unknown despite the fact that sex chromosome constitution – the number of X and Y chromosomes – is the largest source of genetic variation in the human population. A better understanding of the molecular mechanisms by which these genetic differences, in combination with environmental and hormonal factors, result in the vast phenotypic differences seen across the spectrum of sex is critical for developing effective treatment and prevention strategies for disease and addressing historical disparities in research and clinical care.

The goal of the San Roman lab is to uncover the molecular mechanisms of sex differences in human biology. Since sex-biased traits likely have multifactorial etiologies, we leverage powerful technologies of human genetics to dissect the complex variable of sex into its fundamental building blocks. To study how sex chromosome constitution influences cellular phenotypes, we developed a unique human cell line repository from hundreds of individuals that have natural variation in the number of sex chromosomes – from one to four copies of the X chromosome and zero to four copies of the Y chromosome. Using this system, we recently showed that the number of X or Y chromosomes in a cell influences the expression of a remarkable 20% of genes across the genome and discovered key transcription factors on the sex chromosomes that underlie this regulation.