Cell competition in X chromosome usage and disease

The unique biology of the mammalian X-chromosome means that the impact of X-linked genetic variation is sex-specific; while males have a single X-chromosome, females have two. As X-linked sequence variants cause ~600 diseases, having an extra copy can be advantageous. Nevertheless, the manifestation of X-linked traits is highly variable between females. Such variability arises from the random inactivation of one X-chromosome in each female cell, which creates a mosaic of cells that selectively express genetic variants located on either X chromosome. We have recently demonstrated that variants in the X-linked genes Stag2 and Hdac8 can drive cell competition in heterozygous females. Competition profoundly skews the proportion of cells that use one or the other X-chromosome in specific tissues and cell-types. This discovery raises many important questions; how does X-linked competition work, how many other X-chromosome variants drive competition, and how does competition affect the phenotypic manifestation of X-linked traits? Here we propose to address this knowledge gap to uncover how competition impacts female disease susceptibility/resilience. Leveraging human population data, preclinical models and in vitro systems we will systematically evaluate the extent, mechanisms and impacts of X-linked cellular competition in female development and X-linked disease manifestation.