Decoding the Ashkenazi Genome May Offer Clues to Cancer, Diabetes

Study of 1,500 Jews Offers Promising Progress

Thinking Big: Itsik Pe’er, a computational biologist at Columbia University is leading effort to decode 1,500 Ashkenazi Jews.
Courtesy of Albert Einstein College of Medicine
Thinking Big: Itsik Pe’er, a computational biologist at Columbia University is leading effort to decode 1,500 Ashkenazi Jews.

By Elie Dolgin

Published August 05, 2013, issue of August 09, 2013.
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Scientists have long been acutely interested in the genetic idiosyncrasies of Ashkenazi Jews. Like other groups with a long history of marrying from within, Ashkenazim constitute a relatively homogenous population.

This has led to the discovery of a number of genetic alterations, or mutations, that are responsible for diseases found more often in Ashkenazi Jews. Think Tay-Sachs, Gaucher’s or other so-called “Jewish genetic disorders.” But the smaller gene pool has also made it easier for scientists to find genes responsible for widespread ailments with complex genetic underpinnings, such as cancer and diabetes.

To date, such work has been done by looking at only a fraction of the genes in the entire human hereditary complement — usually just a million or so scattered DNA letters. But thanks to advances in gene sequencing technologies, and declining prices in their application, the pursuit of disease-causing mutations affecting Ashkenazim is about to advance by orders of magnitude — up to all 3 billion nucleotides that make up the human genome.

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A group of leading researchers from across the United States and Israel is currently raising money to decode the genomes of more than 1,500 Ashkenazi Jews, including healthy individuals and those suffering from breast cancer, Crohn’s disease, schizophrenia and a handful of other common ailments. Most of these disorders in the academic hot seat are caused by multiple genes that, to date, have eluded scientific discovery.

It’s not that Ashkenazi Jews have more defective DNA or suffer such diseases at appreciably higher rates than other ethnic groups — they do not. Rather, because only a small number of ancestors from Central and Eastern Europe gave rise to the millions of Ashkenazim alive today, scientists like those involved in the nascent Ashkenazi Genome Project can compare healthy and sick Jews and, through statistical techniques, more easily pick out which genetic alterations might explain the medical discrepancies.

“With feasible investment and the sequencing of only hundreds of individuals, one can get very good representation of the genomes of millions of people living today,” says Itsik Pe’er, a computational biologist at Columbia University and one of the scientists who is spearheading the effort. “This is something that you cannot do in many other populations of interest to geneticists.”

Geneticists commonly study reproductively isolated populations. For example, the Old Order Amish and Hutterites are the subjects of active investigation in the United States, and many European island dwellers in Iceland, Sardinia and elsewhere have had their genomes decoded and analyzed. But these groups are relatively small — usually counted in the tens or hundreds of thousands. As a result, it can be hard for scientists — who need robust sample sizes to yield statistically meaningful results — to find sufficient numbers of study participants who suffer from any given disease.

“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.

Dr. Harry Ostrer, a medical geneticist at Einstein, thinks that completing this project will create a blueprint against which anyone — particularly those of Ashkenazi Jewish descent — could compare his or her own genetic data. “We’re going to be increasingly approached by people who say, ‘Okay, I have my genome sequenced. Can you help me understand it?’” he says. “So, our having catalogues of well-annotated variants that say ‘here’s what we know’ is going to be very important to people.”

The consortium hopes to raise between $5 million and $10 million to sequence some 400 to 500 healthy individuals and at least 100 individuals with each of nine different conditions: breast cancer, Crohn’s disease, dystonia (a neurological movement disorder), Parkinson’s disease, diabetes, birth defects, Gaucher’s disease, schizophrenia and bipolar disorder. They also aim to map the genomes of 100 centenarians with extreme longevity and good health.

The organizers have some funding from the National Institutes of Health, the United States-Israel Binational Science Foundation and several private donors, but they are nowhere near their target dollar amount. That’s why the website for the Ashkenazi Genome Project currently serves largely as a portal for collecting donations.

Donors can fund the cost of specialized computers, individual genome reads and staff scientists. Plus, says Lencz, “naming opportunities are available” — either for Lencz’s laboratory or for the entire project.

Smaller donations are welcome, too, but participation is not.

For the project, Lencz and his colleagues are using blood samples collected from previous studies.

Elie Dolgin is a senior news editor for the journal Nature Medicine, in Cambridge, Mass. Contact him at feedback@forward.com


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