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 E67% of any AJ genome with long, identical-bydescent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely E350 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 E12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.

Applying Ancestry and Sex Computation as a Quality Control Tool in Targeted Next-Generation Sequencing

“…Most cases of self-report that was not concordant with the automated algorithm determination could be explained by mixed ancestry, and the remainder were compatible with expected cross-classification between European and Middle Eastern groups. 21,22 Automated k-nearest neighbor analysis is expected to perform poorly in individuals with admixture since they may be placed closest to a group falling between the two parent groups in principal component space. Indeed, all incorrectly assigned Africans and Native Americans had ancestry plots consistent with self-report.…”

“…This finding is consistent with recent work suggesting that the Ashkenazi Jewish background is an approximately even mix of European and Middle Eastern groups. 21,22 Accounting for this overlap between European and Middle Eastern individuals by combining those two groups achieves an overall concordance rate of 98.7%. Of the 154 patients self-reporting mixed ancestry, more than 80% of cases fell into one of three groups: European and Native American (47%), Latin American (21%), and European and Ashkenazi (13%) (Supplementary Table 1; all supplemental materials can be found at American Journal of Clinical Pathology online).…”

Rapidly Registering Identity-by-Descent Across Ancestral Recombination Graphs

“…6 for detailed explanation of the models and the parameters). The latter model is expressive enough to be consistent with some populations that went through a sharp decline in population size in recent history Gusev et al, 2012;Carmi et al, 2014a;Lim et al, 2014;Gauvin et al, 2014). Figure 7 plots the statistic we use for inference, average total IBD-sharing across the cohort, for several constant population sizes across different cohort sizes and cutoffs m for IBD length.…”

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

“…Consequently, distantly related members of the same isolated population may share identical chromosomal segments that descended from a distant common ancestor, known as identity by descent (IBD). This facilitates techniques such as long-range haplotyping, genotype imputation, and construction of population-specific reference panels (Colonna et al 2013;Carmi et al 2014;Gudbjartsson et al 2015). Shared homozygous blocks may be as large as several megabases and contain dozens or hundreds of genes (Puffenberger et al 2012).…”

“…deCODE is studying rare variation at the population level in Iceland, using whole genome sequencing in a subset, augmented with genotype imputation in a larger sample (Gudbjartsson et al 2015). Analogous efforts are underway in Ashkenazi (Carmi et al 2014), Sardinian (Sidore et al 2015), Dutch (Genome of the Netherlands Consortium 2014), and Amish population samples (Crawford et al 2014). A consortium of researchers led by the NIMH is currently developing a whole genome reference panel for use in Anabaptist populations, which include Amish and Mennonites (Hou et al 2015).…”