Competition shapes the landscape of X-linked genetic diversity [scRNA-seq]
Human populations harbour sequence variants even within essential genes. As a result of random X chromosome inactivation (XCI) and epigenetically stable XCI propagation, X-linked variation gives rise to genetically diverse clones that co-exist within XX individuals. Whether interactions between such clones shape the deployment of X-linked diversity remains to be explored. To address this question, we focus on benign coding variation in the X-linked STAG2 gene. Mouse models reveal that clones expressing Stag2 variants contribute to tissues such as skin and brain at the expected frequencies, but show reduced contributions to the haematopoietic stem and progenitor cell pool, and severely defective lymphoid specification. Unexpectedly, the absence of Xvariant clones from the lymphoid compartment is due not to cell-intrinsic defects, but requires competitive interactions with Xwt clones: in the absence of Xwt, Xvariant cells generate normal numbers of functional lymphocytes. X-linked competition has hallmarks of non-cell-autonomous 'cell competition', known to operate in a range of biological processes including embryonic development, aging, and cancer. These findings show that interactions between genetically diverse clones that may operate in any XX individual can shape the contribution of X-linked diversity to specific cell types and tissues. Overall design: Bone marrow cells isolated from heterozygous Stag2-WT x Stag2-R370Q Atrx-Luc/bGal female mice were depleted of lineage markers. FITC+ (Stag2-R370Q) and FITC- (Stag2-WT) cells were sorted and analyzed by scRNAseq.