Mutational recurrence has a marked effect on the frequency spectrum in the ExAC data, resulting in a depletion of singletons at sites with high mutation rates (Figure 2c). We observe a correlation between singleton rates (the proportion of variants seen only once in ExAC) and site mutability inferred from sequence context11 (r = −0.98; p < 10−50; Extended Data Figure 1d): sites with low predicted mutability have a singleton rate of 60%, compared to 20% for sites with the highest predicted rate (CpG transitions; Figure 2C). Conversely, for synonymous variants, CpG variants are approximately twice as likely to rise to intermediate frequencies: 16% of CpG variants are found in at least 20 copies in ExAC, compared to 8% of transversions and non-CpG transitions, suggesting that synonymous CpG transitions have on average two independent mutational origins in the ExAC sample. Recurrence at highly mutable sites can further be observed by examining the population sharing of doubleton synonymous variants (variants occurring in only two individuals in ExAC). Low-mutability mutations (especially transversions), are more likely to be observed in a single population (representing
