Quantifying the somatic evolution occurring in healthy and pre-malignant human tissues*

Many human tissues are maintained by large numbers of long-lived stem cells. Positive and negative selection on somatic mutations that occur in these stem cells can drive rapid evolution in human tissues over timescales of years to decades. Blood is an ideal system for gaining a quantitative understanding of these dynamics because it is easily sampled, less spatially structured relative to other tissues and genomically well characterised. In this talk I will describe how large-scale sequencing data from hundreds of thousands of individuals can be used to provide quantitative estimates for the key parameters governing clonal evolution including the “fitness effects” conferred by specific variants, the mutation rates of alterations and the population sizes of cycling stem cells. These quantitative analyses reveal the majority of events driving clonal expansions in blood (“clonal haematopoiesis”) occur outside of canonical cancer genes suggesting a large number of “missing” driver mutations yet to be discovered. I will show recent work that exploits unique collections of serial blood samples to reveal how expanding somatic clones arise and compete with each other in healthy individuals and in people destined to develop a future leukaemia. These data shed light on the evolutionary dynamics occurring in pre-cancerous stem cells and suggest that many aspects of the observed dynamics can be understood within a surprisingly simple model of the evolutionary dynamics.