Extended Data Fig. 12: Positive selection over life.

Four consecutively simulated phylogenies of 380 cells sampled from a population of 100,000 cells that has been maintained at a constant Nτ over life, with incorporation of positively selected ‘driver mutations’. The driver mutations have a fitness effect > 5% (drawn from a gamma distribution with shape = 0.47 and rate = 34) and enter the population at a rate of 200 per year. These are the maximum posterior density estimates of the rate and shape parameters obtained using the ABC method. The inclusion of these driver mutations is able to recapitulate a similar clade size distribution to that observed in the real HSPC phylogenies of the observed individuals across the whole age range. However, including driver mutations does not fully recapitulate the observed lack of coalescent events in the last 10–15 years of life, showing that an increase in Nτ over this time is also required to fully recreate the patterns of coalescences in the real phylogenies. Driver mutations are marked with a symbol and their descendent clades are coloured. In all cases Nτ is the same as the population size (N) as the generation time (τ) in all simulations is fixed at 1 year. The symbols / colours are not consistent for driver mutations between plots. The largest clades are therefore coloured in a consistent way beneath the plots to show how their size changes over time. The simulated phylogenies illustrate the complex clonal dynamics that can occur in later life as a result of clonal competition. While the majority of clades continue to expand, others stay relatively stable and some reduce in size. The phylogenies also show that by the age of 80 typically > 90% of HSCs in the population carry at least one driver mutation.