A statistical method for quantifying progenitor population reveals incipient cell fate commitments

Abstract Quantifying the number of progenitor cells that founder an organ, tissue or cell population is of fundamental value for understanding the development and homeostasis of a multicellular organism. Previous efforts rely on marker genes that are specifically expressed in progenitors. The strategy is, however, often hindered by the lack of ideal markers. By exploring the cell phylogenetic tree that records the cell division history during development, we here describe a general statistical method able to quantify the progenitors of any tissues or cell populations defined in an organism without progenitor-specific markers. The method, termed targeting coalescent analysis (TCA), computes for all cells of tissue the average coalescent rate at the monophyletic clades of the target tissue, the inverse of which then measures the progenitor number of the tissue. Both theoretical deduction and computer simulations supported the underlying logics of TCA, which was then validated by empirical data of nematode, fruit fly and mouse, all with required cell phylogenetic trees. We further showed that TCA can be used to identify lineage-specific gene expression upregulations during embryogenesis, revealing incipient cell fate commitments in mouse embryos.