Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Distribution of genetic variants across the genome.Common (allele frequency ≥ 0.5%) and rare (allele frequency < 0.5%) variant counts are shown above and below the x axis, respectively, within 1-Mb concatenated segments (see Methods). Segments are stratified by CADD functionality score, and sorted based on their number of rare variants according to the functionality category. There were 22 high CADD, 22 medium CADD and 34 low CADD coding segments, and 40 high CADD, 238 medium CADD and 2,381 low CADD noncoding segments. Noncoding regions of the genome with low CADD scores (<10, reflecting lower predicted function) have the largest levels of common and rare variation (noncoding plot region, dark and light blue, respectively), followed by low CADD coding regions (coding plot region, dark and light blue, respectively). Overall, the vast majority of human genomic variation comprises rare variation.

Characteristics of singleton clustering patterns.Parameter estimates for exponential mixture models of singleton density. Each point represents one of the four components in one of the 3,000 individuals in the sample, coloured according to the genetically inferred population of that individual. The rate parameters of each component are shown across the x axis, and the lambda parameters (that is, the proportion that the component contributes to the mixture) are shown on the y axis (on a log–log scale). Histograms show the distribution of the lambda and rate parameters for each component. AFR, African ancestry; EAS, East Asian ancestry; EUR, European ancestry.

Retained non-reference ancestral sequences discovered from unmapped reads.a, Length distribution of fully resolved ancestral sequences, coloured by overlap with GENCODE v.29 genic features. b, Percentage of non-reference (alternative) alleles compared with the percentage of non-reference sequence identified per individual, coloured by population group. c, Venn diagram showing the positional concordance with insertions identified using short-read data from two previous studies40,41. The number of sequences specific to each study and that have not been partially resolved in the other studies is given between brackets.

Ancestry, genetic diversity and rare-variant genetic relatedness across the TOPMed studies.Each study label is shaded based on their population group. From the outside moving in each track represents: the unrelated sample size of each study used in these calculations, average admixture values, average number of heterozygous sites in each individual’s genome, average number of singleton variants in each individual’s genome and the average within-study rare-variant (RV) sharing comparisons. The links depict the 75th percentile of between-study rare-variant sharing comparisons. All between-study rare-variant sharing comparisons can be found in Supplementary Fig. 29. The sample size, average heterozygosity, number of singletons, within-cohort rare-variant sharing and admixture values by TOPMed study and population group can be found in Supplementary Table 13. Study name abbreviations are defined in Extended Data Tables 1, 2 and Supplementary Table 20.

Relative increase in singletons and doubletons of the site frequency spectrum across McVicker’s B and the population size inferred from demographic inference using various sample sizes.a, The relative increase in the singleton (left) and doubleton (right) bins of the site frequency spectrum for decreasing percentile bins of McVicker’s B compared with the highest percentile bin of B. The higher percentiles of B indicate weaker effects of selection at linked sites (SaLS). These relative increases are plotted for different sample sizes. b, Each point corresponds to the population size inferred in the last generation of an exponential growth model for Europeans. Demographic inference was conducted with different sample sizes for fourfold degenerate sites (n = 4,718,653 sites) and the highest 1% B sites (n = 10,977,437 sites). Error bars show 95% confidence intervals (see Supplementary Table 14 for parameter values). Ne, effective population size.