Synonymous mutations reveal genome-wide driver mutation rates in healthy tissues

Genetic alterations that drive clonal expansions in ostensibly healthy tissues have implications for cancer risk. However, the total rate at which clonal expansions occur in healthy tissues remains unknown. Synonymous passenger mutations that hitchhike to high variant allele frequency due to a linked driver mutation can be used to estimate the total rate of positive selection across the genome. Because these synonymous hitchhikers are influenced by all mutations under selection, regardless of type or location, they can be used to estimate how many driver mutations are missed by narrow gene-focused sequencing panels. Here we analyse the variant allele frequency spectrum of synonymous passenger mutations to estimate the total rate at which mutations driving clonal expansions occur in healthy tissues. By applying our framework to data from physiologically healthy blood, we find that a large fraction of mutations driving clonal expansions occur outside of canonical cancer driver genes. In contrast, analysis of data from healthy oesophagus reveals little evidence for many driver mutations outside of those in NOTCH1 and TP53. Our framework, which generalizes to other tissues, sheds light on the fraction of drivers mutations that remain undiscovered and has implications for cancer risk prediction.