Ashkenazi Jewish Genetics

Genetic studies have shown that the Ashkenazi Jewish (AJ) population (numbering about 10 million individuals worldwide) had undergone a severe medieval bottleneck, followed by an extremely rapid expansion. This demographic history makes the AJ population attractive for disease mapping studies, since deleterious variants may have arisen in frequency in AJ and are thus easier to detect.

The Ashkenazi Genome Consortium (TAGC), of which our lab is a member, has been recently founded to realize the potential of Ashkenazi genetics. We have so far completed the sequencing and analysis of 128 high-coverage complete genomes of healthy AJ individuals (a “reference panel”). Our analysis has established the utility of our reference panel for a number of medical genetics applications, such as carrier screening, clinical genomics, and imputation of missing variants [1,2]. We are in the process of sequencing hundreds of additional genomes.

We have also studied the population genetics of AJ in comparison to other populations [1,3]. Our studies established that the Ashkenazi ancestry draws from an approximately equal mixture of European and Middle-Eastern ancestries, and that AJ had a severe founder event (an effective population size of merely ≈300-400 individuals) around 700 years ago. The admixture in Europe likely happened in two stages, before and after the founder event, with a major contribution from Southern Europeans. We are currently interested in the impact of sex-specific demographic events in the Ashkenazi history.

In parallel, the lab is collaborating on medical studies of specific diseases and conditions (currently schizophrenia, Crohn’s, lipid levels, and age-related macular degeneration; see also [4,5,6]). One goal of the lab is to develop efficient methods that leverage the unique AJ demographic history for accurate inference of Ashkenazi genomes that were only sparsely sequenced. A particular application of interest is pre-implantation genetic testing, where genetic material is extracted and sparsely sequenced from single embryonic cells.

[1] Carmi et al., Nature Communications, 2014 (link)
[2] Baskovich et al., Genetics in Medicine, 2016 (link)
[3] Xue et al, PLoS Genetics, 2017 (link)
[4] Quint et al., European Journal of Medical Genetics, 2016 (link)
[5] Jaron et al., Clinical Genetics, 2016 (link)
[6] Vijai et al., Cancer Discovery, 2016 (link)

A reconstruction of the Ashkenazi Jewish and European demographic history using DNA sequence data. (AJ: Ashkenazi Jews; FL: Flemish from Belgium). The upper part shows the reconstruction of the ancient history of these populations, while the lower part illustrates the recent AJ history. Horizontal arrows correspond to effective population size. The wide arrow represents a migration event. The ancient reduction in population size on the left side likely corresponds to an Out-Of-Africa event and the formation of the Middle-Eastern population. This was followed by the divergence of Europeans, members of which later migrated into the Ashkenazi population. From Carmi et al., Nat. Commun., 2014.

The pattern of lengths of shared segments in Ashkenazi Jews (AJ) cannot be explained by a constant population size, but is very well fitted into a population undergoing a severe bottleneck (decrease in the population size) followed by rapid expansion. From Carmi et al., Nat. Commun., 2014.

The lengths of shared segment in Ashkenazi Jews (AJ). The observed pattern in AJ cannot be explained by a constant population size, but is very well fitted into a population undergoing a severe bottleneck (reduction in population size) followed by rapid expansion. From Carmi et al., Nat. Commun., 2014.