The relative numbers of singletons, doubletons and other very rare variants can be used to infer human demographic history11,55,56. Although much of demographic inference in past studies focused on fourfold degenerate synonymous sites in protein sequences, these sites evolve under the influence of strong selection at nearby protein-coding sites57,58, which can affect the inferred timing and magnitude of population size changes59. WGS enables us to access intergenic regions of the genome that are minimally affected by selection. We measured how the site frequency spectrum and demographic inference changed as a function of sample size and an index of selection at linked sites (McVicker’s B statistic60) using TOPMed individuals whose genomes suggested mostly European ancestry and low admixture. Estimates of effective population size of European individuals based on the 1% of the genome with the weakest effect of selection at linked sites consistently yielded around 1.1 million individuals (Fig. 5, Supplementary Figs. 34, 35 and Supplementary Table 14).
