Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Abstract

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈ 67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈ 350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈ 12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.

Figure 1. Novel variants discovered in Ashkenazi Jewish and Flemish genomes.

(a) Variant counts (all and heterozygous; left) and fraction novel (right) per genome in the Ashkenazi Jewish (AJ) and Flemish (FL) cohorts (corresponding to about ≈80% of the raw variants remaining after QC and cohort merging; Supplementary Note 2; error bars represent s.d.). (b) Efficiency of filtering all novel variants detected in an AJ personal genome, measured by counting those that remain new after filtering such a genome against either FL or AJ panels of a matched size (n=26) or our complete AJ panel (n=127). Left: all novel variants; right: non-synonymous novel variants. Error bars represent s.d. (c) The number of newly discovered segregating sites in AJ and FL versus the number of already sequenced individuals in each cohort (markers). Dashed and solid lines are expectations based on either a constant size or a bottleneck and growth model (bn/growth), respectively, fitted to each population separately (Supplementary Note 3). The inset magnifies the region (0, 10).

Figure 2. Utility of the AJ reference panel in IBD-based and traditional imputation.

(a) The distribution, over all pairs of individuals, of the fraction of the genome shared IBD (segment lengths >3 cM) either within AJ, within FL or between AJ and FL. (b) The average fraction of a genome (in AJ and CEU) where at least one haplotype is covered by segments shared with a population-matched panel. Data points (markers) were fit to (lines), where c is the average coverage and n is the number of individuals in the panel (Supplementary Note 4). (c) The aggregate r² (over the AJ study genomes) between the true and the imputed dosages versus the minor allele frequency, when imputing an AJ genome using a reference panel consisting of either AJ or CEU genomes.

Figure 3. The AFS and the lengths of shared segments.

(a) The (normalized) minor allele frequency spectrum in AJ and FL, shown as counts in subsets of n=25 genomes in each cohort. The green line corresponds to the expectation in a constant-size population (Wright–Fisher), and bars represent deviations in AJ and FL. The inset shows the spectra of alleles private to each population. (b) A heat map of the joint (minor) allele frequency spectrum of AJ and FL (lower left triangle) compared with the expected joint AFS, had population labels been random (upper right triangle). (c) The average fraction of the genome found in shared segments versus the segment length (AJ only; circles), along with the best fit to a recent bottleneck and growth model (solid blue line; Fig. 4) and the expectation in a constant-size population with the same total sharing (dashed green line).

Figure 4. A reconstruction of the AJ and FL demographic history.

The upper part of the diagram shows the reconstruction of the ancient history by fitting the joint AFS (Fig. 3b) using ∂a∂i and using a mutation rate of 1.44 × 10⁻⁸ per generation per bp. The lower diagram shows the recent AJ history, reconstructed by fitting the IBD length decay pattern (Fig. 3c). The wide arrow represents an admixture event; all effective population sizes (horizontal arrows) are in number of diploid individuals; all times were computed assuming 25 years per generation. Confidence intervals are provided in Supplementary Tables 6 and 7.