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.

X 染色体失活 (XCI) 在 XX 个体内产生克隆异质性。与人类 X 染色体之间的序列变异相结合，XCI 产生了个体内克隆多样性，从而两组克隆表达一条或另一条 X 染色体上存在的相互排斥的序列变异。在这里，我们询问这些克隆是否只是共存或潜在地相互作用，以调节 X 连锁多样性对生物体发育的贡献。重点关注人类STAG2基因中的 X 连锁编码变异，我们发现Stag2^变体克隆以预期频率对大多数组织做出贡献，但在Stag2 ^WT Stag2^变体小鼠模型中无法形成淋巴细胞。出乎意料的是，淋巴区室中不存在Stag2^变异克隆不仅是由于细胞内在缺陷，而且需要Stag2 ^WT克隆的持续竞争。这些发现表明，表观遗传多样性克隆之间的相互作用可以在 XX 个体中发挥作用，以细胞类型特异性的方式塑造 X 连锁遗传多样性的贡献。