From: Gina Miller (nanogirl@halcyon.com)
Date: Mon Jun 07 1999 - 00:27:31 MDT
Building Detailed Map Of Human DNA Will Take More Time And Resources Than
Previously Thought, Says Hutch Researcher
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 http://www.fhcrc.org
Gina "Nanogirl" Miller
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