Charting single-cell lineages with synthetic and natural barcodes

Across our lifespan, cells divide and differentiate to create the functional units of all organs, yet with age and cancer a small number of cellular families (clones) will rule the fate of the organism. Advances in synthetic and natural barcoding methods now enable cellular ancestries to be reconstructed with unprecedented single-cell resolution. These single-cell lineage-tracing studies are leading to a re-evaluation of long-standing paradigms in development, ageing and cancer biology and are revealing the underpinnings of phenotypic heterogeneity for various cellular functions, including regeneration and stress responses. Despite remaining methodological challenges, progress continues towards multimodal tracing methods that combine spatial, genetic, epigenetic and transcriptomic information. The future transition of clonal analysis into the clinic may eventually help detect, predict and prevent disease progression. In this Review, Rodriguez-Fraticelli and Parreno discuss advances in single-cell lineage-tracing methods and how their application to diverse biological processes, such as development, ageing and cancer, is challenging prevailing views and providing new insights.