Many diseases show sex differences in incidence or progression, suggesting that one sex has inherent biological factors that protect from or exacerbate disease. Historically the root causes of all sex differences in tissue phenotypes were thought to be the gonadal hormones. The advent of specialized mouse models has uncovered non-hormonal origins of sex bias in disease, caused by inherent inequality of XX vs. XY sex chromosomes. For example, the Four Core Genotypes and XY* models allow the investigator to compare mice with different sex chromosomes, but with the same type of gonad. Use of these mouse lines in several models of disease has now progressed far enough that specific X or Y genes have been identified that give rise to molecular cascades causing sex differences in disease. The number of X chromosomes, one vs. two, causes sex differences in models of metabolism and adiposity, of autoimmune disease, of Alzheimer’s disease, and bladder cancer. The underlying genes that cause the X chromosome effects are X-linked Kdm5c and Kdm6a, two lysine demethylases acting on H3K4 to activate or reduce gene expression elsewhere in the genome. The genes escape X inactivation and are expressed from all X chromosomes, so that XX cells express a higher dose than XY cells. This inherent inequality influences diverse tissues and diseases. Just as the discovery of gonadal hormonal sex-biasing factors, such as testosterone and estradiol, catalyzed waves of discovery of downstream mechanisms leading to sexual dimorphism in many tissues, we now expect the discovery of new sex chromosomal sex-biasing factors to lead to new research on novel pathways causing sex differences in diverse tissues related to numerous diseases. Supported by NIH grants OD026560, HD100298, HD076125, DK083561, HL1311820
1. Understand mouse models that test inherent sex differences in X and Y gene dose that cause sex differences in disease.
2. Appreciate new evidence about specific X genes that are the origins of sex bias in the genome.