Quantitative fate mapping: Reconstructing progenitor field dynamics via retrospective lineage barcoding

Natural and induced somatic mutations that accumulate in the genome during development record the phylogenetic relationships of cells; however, whether these lineage barcodes can capture the dynamics of complex progenitor fields remains unclear. Here, we introduce quantitative fate mapping, an approach to simultaneously map the fate and quantify the commitment time, commitment bias, and population size of multiple progenitor groups during development based on a time-scaled phylogeny of their descendants. To reconstruct time-scaled phylogenies from lineage barcodes, we introduce Phylotime, a scalable maximum likelihood clustering approach based on a generalizable barcoding mutagenesis model. We validate these approaches using realistically-simulated barcoding results as well as experimental results from a barcoding stem cell line. We further establish criteria for the minimum number of cells that must be analyzed for robust quantitative fate mapping. Overall, this work demonstrates how lineage barcodes, natural or synthetic, can be used to obtain quantitative fate maps, thus enabling analysis of progenitor dynamics long after embryonic development in any organism.