Lineage tracing in human tissues

The dynamical process of cell division that underpins homeostasis in the human body cannot be directly observed in vivo, but instead is measurable from the pattern of somatic genetic or epigenetic mutations that accrue in tissues over an individual's lifetime. Because somatic mutations are heritable, they serve as natural lineage tracing markers that delineate clonal expansions. Mathematical analysis of the distribution of somatic clone sizes gives a quantitative readout of the rates of cell birth, death, and replacement. In this review we explore the broad range of somatic mutation types that have been used for lineage tracing in human tissues, introduce the mathematical concepts used to infer dynamical information from these clone size data, and discuss the insights of this lineage tracing approach for our understanding of homeostasis and cancer development. We use the human colon as a particularly instructive exemplar tissue. There is a rich history of human somatic cell dynamics surreptitiously written into the cell genomes that is being uncovered by advances in sequencing and careful mathematical analysis lineage of tracing data. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.