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“The Ashkenazim have the advantage that if you reach worldwide there are millions of them, whereas in other [genetically similar] founder populations there are fewer,” says Dr. Alan Shuldiner, director of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine in Baltimore, who studies Amish populations but is not involved in the Ashkenazi project.
Ashkenazi Jews “are on the Goldilocks end of populations” — just right — Pe’er notes.
By reading every last DNA letter from this cohort, Pe’er and his collaborators have three goals in mind: to get a better grasp of the genetic ancestry of Ashkenazim; to learn about the root causes of disease, and ultimately to apply that knowledge to improve medical practice.
“The Ashkenazi Genome Project has the unique ability to advance all three of those in a more inexpensive and a more efficient manner than most other approaches that are currently available,” says project co-leader Todd Lencz, a clinical psychologist at the Feinstein Institute for Medical Research, a research arm of the North Shore-Long Island Jewish Health System in Manhasset, N.Y. “If we can meet our goal, we could really have some answers in a few years. This is not a 20-year project.”
Pe’er and Lencz’s group calls itself The Ashkenazi Genome Consortium — or TAGC — an acronym that plays off the four “letters” of the genetic code (thymine, adenine, guanine and cytosine). Thus far, the consortium has sequenced the genomes of 137 individuals. The researchers reported on the first 57 of those in November 2012 at the American Society of Human Genetics’ annual meeting in San Francisco. They showed that by comparing Ashkenazi samples with each other they could whittle the 3 billion base pairs of the human genome down to some 30,000 letters that might actually play a part in contributing to disease. Now they plan to sequence many more Ashkenazim to study the genome even more closely.
“The ability to look at the genome and get rid of 95 to 99% of the fluff of the background noise is a make-or-break in terms of finding mutations that are responsible for particular genetic conditions,” says Pe’er.
The preliminary analysis also revealed that some 30 to 35 generations ago — equivalent to less than 1,000 years — Ashkenazim underwent what geneticists call an extreme “bottleneck.” This means that the 11 million Ashkenazi Jews alive today descend largely from only around 400 individuals who lived in the Middle Ages. Comparing the Ashkenazi genome sequences with those derived from individuals of other ethnic origins also showed that these “founder” Jews probably lived in the Levant, a geographic region that now includes Israel and several of its Arab neighbors.
It’s not that these demographic findings are radically different from what scientists had already deduced from more limited DNA datasets. But, says Lencz, “there’s definitely more that we can learn by drilling all the way down into the whole genome.”
In addition to the leaders at Feinstein and Columbia, the consortium includes scientists from several other New York area institutions, including Mount Sinai Medical Center, Albert Einstein College of Medicine and the Memorial Sloan-Kettering Cancer Center. Elsewhere, investigators at Yale University, the Massachusetts Institute of Technology and Hebrew University are also contributing.