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FEATURE: What s in a SNP? Israeli Start-Up Searches Ashkenazi Jews for Answers

JERUSALEM, Dec 8 – The scientific argument about whether population genetics studies should be based on homogenous or heterogeneous groups of people has given rise to a number of companies on either side of the debate.

Now a new start-up, IDGene Pharmaceuticals, has taken the debate to a new extreme, claiming that the population they have chosen to study is among the most homogenous out there.

Based in Jerusalem, IDGene has begun to collect tissue samples from Ashkenazi Jews, or Jews of European descent, who, according to Ariel Darvasi, president and chief scientific officer of the company, will help to elucidate the underlying genetic basis of many diseases, including diabetes, breast cancer, multiple sclerosis, schizophrenia, hypertension, and asthma.

“There have been a few papers that claimed that there might be little or no advantage to using homogenous populations for this purpose; our conclusion is that the advantage may be quite significant,” said Darvasi, during a tour of his sleek Jerusalem offices, which are still awaiting the arrival of the SNP detection systems that will provide the backbone of the company’s activity.

According to Darvasi, there are three main advantages to studying highly homogeneous populations, including a higher level of linkage disequilibrium, or the correlation between two polymorphic points that are physically very close to one another on the DNA.

“Is this advantage great or not?” Darvasi asked rhetorically. “At first we thought it was not great, but within the Ashkenazi population it will be consistent. We have initial, unpublished results that indicate the linkage disequillibrium in our population is greater even for polymorphisms that are common.”

Such a phenomenon indicates lower genetic variability within a population and increases the number of markers that can be used to study specific groups of people.

Reduced genetic variation within a homogeneous population also helps to lower the amount of genetic background noise, which can cloud studies, Darvasi said.

And, he added, studies of homogeneous populations result in fewer false positives since allele frequencies are more balanced between the test group and the control group.

Who’s More Homogeneous?

So, what does IDGene have that Decode Genetics of Iceland does not?

According to Darvasi, the Ashkenazi Jews are even more homogenous than their Icelandic counterparts, having evolved from a population bottleneck that occurred some five centuries ago in Ashkenaz, Germany.

“About 500 years ago there were a few thousand individuals [Ashkenazi Jews], maybe 5,000 in the region,” Darvasi said. “The core population of people who were the founders of today’s Ashkenazim may have been as low as 1,500 people.”

An article in the August 2000 issue of Nature Genetics seems to back up at least part of that claim. In “Genetic Homogeneity of Icelanders: Fact or Fiction?” authors Einar Arnason, Hlynur Sigurgislason, and Eirikur Benedikz argued that Icelanders are among the most genetically variable Europeans.

While Kari Stefansson, CEO of DeCode, disagrees with these findings in a counter argument he made in this month’s Nature Genetics , he also asserts that homogeneity is less important than genealogy in correlating SNPs to disease.

“The importance is in how the information flows from one generation to the next,” said Stefansson. “We are working with the genealogy of the entire nation.”

DeCode has so far collected DNA from over 40,000 of the country’s inhabitants and genotyped over 33,000 samples.

Nevertheless, Darvasi stands firmly by his strategy, adding that the existence of some two million Ashkenazi Jews in Israel today will also make it possible for Israeli scientists to conduct powerful association studies rather than weaker linkage studies to correlate genetics and disease.

“Linkage analysis correlates markers with genes by analyzing how a SNP is passed through a family,” Darvasi said. “Association analysis allows us to study SNPs on the population level.”

Doron Lancet, head of the Crown Human Genome Center at Israel’s Weizmann Institute of Science and a member of IDGene’s scientific advisory board, echoed this sentiment.

“Association studies allow you to sample random members of the population and then look at specific genetic markers,” Lancet said. “If you do the comparison in the right way, you can detect” important genetic information.

“Ariel is using a systematic approach and bringing in the money to do this on a large scale,” Lancet added.  

Putting the Strategy to Work

In order to conduct these studies, Darvasi, who has degrees in both computer science and biology and spent two years at SmithKline Beecham in England before striking out on his own, is looking to begin operations by collecting some 1,000 samples per disease for 17 diseases.

He has so far collected a total of 3,000 DNA samples and expects to gather a total of 20,000.

Darvasi said that IDGene, which has raised a total of $10 million from the Wellcome Trust, Apax Europe, and Jerusalem-based venture capital firm Israel Seed Partners, has already purchased the company’s first set of PCR machines from MWG Biotech and is currently shopping for SNP scoring systems. He is looking at systems developed by Qiagen, Sequenom, Orchid, Third Wave Technologies, MWG, and Pyrosequencing.

He also said that IDGene was trying to develop ways to combine technology it develops in-house with pre-existing technologies in order to be able to do genome-wide SNP scans.

Darvasi said he planned to begin SNP scoring in the next two to three months. Within eight months, IDGene hopes to have high-throughput SNP detection systems operating in house.

The company will use high-density SNP maps, retrieved from the SNP consortium , to serve as the basis for the company’s association-based strategy for gene identification. Additionally, Darvasi said IDGene would also gather DNA samples from Caucasians in the United States in order to run comparative studies.

IDGene, which currently employs 20 people and plans to increase its staff to as many as 35 within two months, will initially make its bread and butter by selling its data to big pharma. Later, the company hopes to apply its data to become a drug developer.

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