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Cross-tissue analysis of allelic X-chromosome inactivation ratios resolves features of human development

X-chromosome inactivation (XCI) is a random, permanent, and developmentally early epigenetic event that occurs during mammalian embryogenesis. We harness these features of XCI to investigate characteristics of early lineage specification events during human development. We initially assess the consistency of X-inactivation and establish a robust set of XCI-escape genes. By analyzing variance in XCI ratios across tissues and individuals, we find that XCI is completed prior to tissue specification and at a time when 6-16 cells are fated for all tissue lineages. Additionally, we exploit tissue specific variability to characterize the number of cells present at the time of each tissue’s lineage commitment, ranging from approximately 20 cells in liver and whole blood tissues to 80 cells in brain tissues. By investigating variance of XCI ratios using adult tissue, we resolve key features of human development otherwise difficult to ascertain experimentally and develop scalable methods easily applicable to future data.