Demographic history and rare allele sharing among human populations

Abstract

High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2-4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.

Fig. 1.

The two-population joint SFS from panels of Chinese individuals from Beijing (CHB) and Yoruba individuals from Ibadan, Nigeria (YRI) for variants occurring in less than 15 of 100 sequenced chromosomes in both panels. Of the 3,366 variants in the overlap of the two panels, all but 194 sites are private to a single population.

Fig. 2.

Joint allele SFSs (all sites) for selected pairs of populations from the exome sequencing panel (Left) compared with expected spectra under site by site population label permutation (Center). Shown are sites occurring in, at most, 15 of 100 chromosomes. All population pairs, including two different panels of Chinese individuals sampled in Beijing, China and Denver, Colorado (CHB and CHD), as well as two groups of European origin (CEU and Tuscans from Italy, or TSI), show substantial residuals for rare variants (Right), consistent with reduced sharing. White bins contain less than one count.

Fig. 3.

The probability that two individuals carrying an allele of given minor frequency come from different populations, normalized by the expected frequency in a panmictic population, using the seven panels of the exome capture dataset. Sharing decreases dramatically as frequency approaches zero. The reduction in sharing at 50% frequency in some population pairs is caused by low overall numbers in that bin, and a single site (rs6662929) that exhibits inconsistent calls between different calling platforms and most likely has an incorrect homozygous reference call in some populations. Sites were binned by frequency: dots indicate the center of each bin, and solid lines are to guide the eye. Note that singletons are not shown, because there can be no sharing for such sites.

Fig. 4.

An illustration of the inferred demographic model, with line width corresponding to population size and time flowing from left to right. The width of the red arrows is proportional to the migration intensity. Model details are provided in Table 2 and ref. .

Fig. 5.

Observed and projected numbers of synonymous and nonsynonymous variants in CEU, CHB + JPT, and YRI as a function of the sample size (two times the number of individuals sequenced). Long and short dashes correspond to jackknife and model-based projections for synonymous sites, respectively. The dotted lines are jackknife projections for nonsynonymous sites. Discrepancies between projections are accounted for by the difference between the model prediction and observed number of singletons in the data.