Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios

The distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells, however the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics that yields the selective coefficients from individual driver mutations from dN/dS estimates, and then measure the DFE for somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 mutants (proliferative bias 1-5%). Accurate measurement of the per-gene DFE in cancer evolution is precluded by the quality of currently available sequencing data. This study provides the theoretical link between dN/dS values and selective coefficients in somatic evolution, and reveals the DFE for mutations in human tissues.