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Researchers Develop Ashkenazi Jewish Reference Panel, Describe Population History

NEW YORK (GenomeWeb) – By sequencing the complete genomes of 128 people of Ashkenazi Jewish ancestry, a team of researchers from New York, Israel, and elsewhere developed a database of variants in the population.

The research team also reported in Nature Communications today that its panel of Ashkenazi genomes exhibited more novel and population-specific variants as compared to a set of European genomes. The researchers suggested that their collection would aid in the clinical interpretation of genome sequences.

"Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes," Itsik Pe'er, associate professor of computer science at Columbia University, said in a statement. "With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders."

Pe'er and his colleagues additionally used the sequences they generated to examine Ashkenazi Jewish population history, finding the population to be a nearly even mix of European and Middle Eastern ancestral populations.

To produce this genome panel, the researchers selected 128 people of self-reported and empirically validated Ashkenazi Jewish ancestry for sequencing. Sequencing by Complete Genomics yielded genomes of more than 50x coverage and uncovered some 12 million high-quality SNPs, 2.9 million of which were novel.

The researchers compared their genome panel to a set of more than two dozen Flemish genomes, finding that the Ashkenazi Jewish genomes had a slightly higher number of variants and a much higher percentage of novel variants.

This suggested to the researchers that, in a clinical setting, genomes obtained from patients of Ashkenazi Jewish descent would be more efficiently screened against this reference panel.

They reported that having an ancestry-matched reference panel improved imputation among the target population. To test this, they split their cohort into a reference panel of 50 genomes — masking all variants not usually called on a SNP array — and a study panel. They then imputed that study panel using either the 50-genome reference panel or the larger 1,000 Genomes reference panel of Europeans living in Utah.

The Ashkenazi Jewish panel, they reported, was more accurate than the European one, with a lower percent of discordant genotypes and an increased correlation between true and imputed dosages.

This improvement in imputations, Pe'er and his colleagues said, is likely due to both increased segmental sharing among people of Ashkenazi Jewish descent and the larger number of Ashkenazi Jewish-specific alleles.

Pe'er and his colleagues also sought to examine the population history of Ashkenazi Jews. Using allele frequency spectra, they found that both the Ashkenazi Jewish and Flemish data supports an ancient population bottleneck some 60,000 years to 86,000 years ago followed by slow exponential growth. It also uncovered asymmetric gene flow from European to Ashkenazi Jewish populations.

Then by folding in analysis of long identity-by-descent segments, the researchers found evidence of a recent Ashkenazi Jewish bottleneck some 25 generations to 32 generations ago and subsequent rapid expansion.

The researchers then developed a model in which they suggest that the contemporary Ashkenazi Jewish population formed between 600 years to 800 years ago — around the time of the bottleneck that whittled the group down to some 250 individuals to 420 individuals — through the fusion of two ancestral populations.

The ancestral European population contributed between 46 percent and 50 percent of the Ashkenazi Jewish gene pool, the researchers noted, and the ancestral Middle Eastern population the rest.

The ancestral European population itself went through a population bottleneck of some 3,500 individuals to 3,900 individuals about 20,400 years to 22,100 years ago, around the time of the Last Glacial Maximum.

The ancestors of both the ancestral European population and the ancestral Middle Eastern population underwent another bottleneck of between 3,600 founders to 4,100 founders some 85,000 years to 94,000 years ago, likely corresponding to an out-of-Africa event, the researchers said.

"Our analysis shows that Ashkenazi Jewish medieval founders were ethnically admixed, with origins in Europe and in the Middle East, roughly in equal parts," Shai Carmi, a post-doctoral scientist at Columbia, said in a statement. "[W]e believe the data settle the dispute regarding European and Middle Eastern ancestry in Ashkenazi Jews."

She added that these results also shed light on European population history. "[O]ur data provides evidence for today's European population being genetically descendant primarily from late mid-eastern migrations that took place after the last ice age, rather than from the first humans to arrive to the continent, more than 40,000 years ago."

The researchers noted in their paper that the times and population sizes they reported are dependent upon the human mutation rate.

Pe'er and his team said that they are now searching for the modern-day populations in Europe and the Middle East that are most similar to the Ashkenazi founders as well as examining how the admixture process took place and whether it was sex-biased. They are also working to sequence more Ashkenazi Jewish individuals.