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Building detailed map of human DNA will take more time and resources than previously thought, says hutch researcher

Article in June issue of Nature Genetics also questions the much-touted value of so-called 'isolated' populations, such as that of Iceland, for mining the gene pool

SEATTLE -- A Fred Hutchinson Cancer Research Center geneticist asserts in the June issue of Nature Genetics that building a detailed map of the human genome will take significantly more time and resources than previously estimated.
     While current gene-mapping efforts target the identification of 400,000 genetic markers to help locate common disease genes, many more such signposts must be found before the map can be considered a truly useful tool for pharmaceutical research and development, says the paper's author, Dr. Leonid Kruglyak.
     "An essential issue yet to be settled is the required marker density for such maps," writes Kruglyak, an associate member of the Hutchinson Center's divisions of Human Biology and Public Health Sciences.
     Kruglyak predicts researchers instead will need to locate at least half a million such "mile markers"along the DNA highway if geneticists are to stay on track when chasing down genes that influence characteristics such as disease susceptibility and drug response.
     "People may be disappointed in my conclusion, because it implies we're going to have to work that much harder, but it is simply a prediction for what resources will actually be needed to accomplish the task ahead of us," says Kruglyak, an expert in using powerful statistical and computational tools to tease out genetic components of common "diseases of civilization" such as cancer and heart disease.
     "The technology for doing this -- typing potentially thousands of individuals for half a million genetic markers -- really needs to be developed much further than where it is today," he says.
     The publication of Kruglyak's paper comes on the heels of the establishment of the SNP Consortium, an unprecedented collaboration between industry and academia to create a finely detailed map of the human genome. Comprised of 10 of the world's largest drug companies, a major British charity and a handful of academic genetics laboratories, this nonprofit alliance, announced in April, seeks to build on and ultimately accelerate the efforts of the federally funded Human Genome Project.
     While the Human Genome Project aims to assemble a common, "one-size-fits-all" map of human DNA sequence by the year 2003, the drug-company consortium plans to take the genetic decoding effort a step further. Its goal: to create a more detailed genetic blueprint that can be used by pharmaceutical companies to tailor medications to a person's unique genetic inheritance -- a radical departure from today's blanket approach to drug design.
     To accomplish this task, the consortium plans to locate, within the next two years, 300,000 of the estimated 2 million single-nucleotide polymorphisms, or SNPs, that pepper the human genome. SNPs (pronounced "snips") are minute, usually functionless single-letter variations within the genetic code that serve as markers, or signposts, to help locate common disease genes. The Human Genome Project, in contrast, seeks to isolate just 100,000 such markers.
     While together these efforts represent a sound start for building a complete, high-density picture of the complete human DNA sequence, even more genetic markers must be found, says Kruglyak, also a professor of genetics and molecular biotechnology at the University of Washington.
     But far from being pessimistic, Kruglyak views the undertaking with much enthusiasm and hope.
     "Having a more finely tuned outline of the human genome in hand ultimately will shed light on what makes each person genetically unique and thus particularly vulnerable to certain diseases or immune to certain drugs," he says.
     Also in the Nature Genetics article, Kruglyak addresses the inherent limitations of mining so-called "isolated" human populations, such as that of Iceland, for disease genes.
     Since Iceland essentially has had no immigration since the Vikings landed in the ninth century, geneticists widely presumed the DNA of its inhabitants would be relatively undisturbed, free of the genetic "static" commonly seen in more culturally diverse populations. With less background noise, it was presumed that gene hunters could more easily zero in on their prey.
     "For geneticists, part of the appeal of isolated populations such as Iceland was that you might be able to get away with a much looser genetic map containing fewer SNPs, or genetic markers," he says. "However, my research shows that in regions surrounding common genetic mutations, the DNA from Iceland looks exactly the same as that from larger populations, requiring an equally dense map of SNPs to detect an association between a marker and disease."
     To be truly homogenous, or free of "background noise," a population must be founded by fewer than 100 people, Kruglyak estimates. Iceland, in contrast, sprung from a migration of more than 10,000 people.
     Prior to his arrival last year at the Hutchinson Center, Kruglyak spent five years as a research scientist in the laboratory of renowned geneticist Dr. Eric Lander, director of the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research in Cambridge, one of five genetic laboratories participating in the Chicago-based SNP Consortium.
     While at the Whitehead, Kruglyak participated on the team that in 1995 unveiled the first detailed map of the human genome ­ a feat that catapulted the $1 billion, 15-year Human Genome Project ahead of schedule by at least two years.
     In late January, Kruglyak became one of 10 young scientists worldwide to receive a $1 million research fellowship from the St. Louis-based James S. McDonnell Foundation, established by the late aerospace research pioneer of the same name.
     Categories in the rigorous international competition for the James S. McDonnell Centennial Fellowship ­ a one-time grant that honors the 100th anniversary of McDonnell's birth ­ ranged from astrophysics and cosmology to human genetics. Kruglyak, one of two winners in genetics, accepted his award in April in Washington, D.C.
     The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. One of 35 National Cancer Institute-designated comprehensive cancer centers in the nation, it is the only one in the Northwest. For more information, visit the Center's Web site at <www.fhcrc.org>

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Editor's note: Dr. Kruglyak is available for interviews through Monday, May 31. To schedule an interview, contact Kristen Woodward at (206) 667-5095. Photographs of Kruglyak also are available upon request.
     To obtain a copy of the Nature Genetics article, entitled "Prospects for Whole-Genome Linkage Disequilibrium Mapping of Common Disease Genes," please contact the journal at (212) 726-9314.

CONTACT:
Kristen Woodward
(206) 667-5095

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