How X-linked sequence variation shapes organismal development

This is a hybrid event - with the speaker attending in-person and viewable on Teams.

X chromosome inactivation (XCI) generates clonal heterogeneity within XX individuals. Combined with sequence variation between human X chromosomes, XCI gives rise to intra-individual clonal diversity, whereby two sets of clones express mutually exclusive sequence variants present on one or the other X chromosome. Here we ask whether such clones merely co-exist, or potentially interact with each other to shape the contribution of X-linked diversity to organismal development. To address this question, we focus on X-linked coding variation in the human STAG2 gene. Stag2variant clones contribute to most tissues at the expected frequencies, but fail to form lymphocytes in Stag2wild-type Stag2variant mouse models. Unexpectedly, the absence of Stag2variant clones from the lymphoid compartment is due not solely to cell-intrinsic defects, but requires continuous competition by Stag2wild-type clones. These findings show that interactions between epigenetically diverse clones, which may operate in any XX individual, can shape the contribution of X-linked genetic diversity to specific cell types and tissues.