Deleterious variants are expected to have lower allele frequencies than neutral ones, due to negative selection. This theoretical property has been demonstrated previously in human population sequencing data12,13 and here (Figure 1d, Figure 1e). This allows inference of the degree of selection against specific functional classes of variation: however, mutational recurrence as described above indicates that allele frequencies observed in ExAC-scale samples are also skewed by mutation rate, with more mutable sites less likely to be singletons (Figure 2c and Extended Data Figure 1d). Mutation rate is in turn non-uniformly distributed across functional classes - for instance, stop lost mutations can never occur at CpG dinucleotides (Extended Data Figure 1e). We corrected for mutation rates (Supplementary Information Section 3.2) by creating a mutability-adjusted proportion singleton (MAPS) metric. This metric reflects (as expected) strong selection against predicted PTVs, as well as missense variants predicted by conservation-based methods to be deleterious (Figure 2e).
