Competition shapes the landscape of X-chromosome-linked genetic diversity

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 modulate the contribution of X-linked diversity to organismal development. Focusing on X-linked coding variation in the human STAG2 gene, we show that Stag2^variant clones contribute to most tissues at the expected frequencies but fail to form lymphocytes in Stag2^WT Stag2^variant mouse models. Unexpectedly, the absence of Stag2^variant clones from the lymphoid compartment is due not solely to cell-intrinsic defects but requires continuous competition by Stag2^WT clones. These findings show that interactions between epigenetically diverse clones can operate in an XX individual to shape the contribution of X-linked genetic diversity in a cell-type-specific manner.