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”), and 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 a few more hundreds of additional genomes.

We have also studied the population genetics of AJ in comparison to other populations [1]. Our study established that the Ashkenazi ancestry draws from an approximately equal mixture of European and Middle-Eastern ancestries. A reconstruction of the recent AJ history suggested an effective population size of merely ≈350 individuals around 700 years ago. Current work is focused on finer modeling of the population’s history, specifically, quantifying the source, time, and duration of the European gene flow into the early Ashkenazi Jews.

In parallel, the lab is working with collaborators on medical studies of specific diseases and conditions (including schizophrenia, Crohn’s, lipids, and longevity). One general goal is to develop an efficient method, tailored to the particular AJ demographic history, that will enable the accurate inference of Ashkenazi genomes that were only sparsely sequenced (see also here). Thousands of such genomes are available (with many more to come), and therefore, a new method will make feasible the implementation of very large association studies.

The rich genomic data accessible to the lab provides an extremely interesting case study for our theoretical and methodological studies in population genetics (see here and here). For example, we can use our new methods to refine our understanding the Ashkenazi history, and in particular, the nature of the medieval founder event. Other newly developed methods can be used, for example, to estimate the time of origin (and selection pressure) on AJ disease mutations or detect gene conversion tracts.

[1] Carmi et al., Nature Communications, 2014 (link)
[2] Baskovich et al., Genetics in Medicine, 2015 (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.