Kruglyak to describe studies of genetic variation and disease

When the Human Genome Project (HGP) is completed, scientists will hold the blueprint in their hands for all human life. Most of us have heard this statement before. But keep your ears open. As the achievement of this monumental task nears, cliches are being replaced with fresh metaphors. Scientists are stressing that a new period of discovery is about to begin. It is almost time to begin comparing our carbon copies.

Leonid Kruglyak

Once the sequence of the human genome is determined, researchers will begin to identify genetic variation among individuals and determine which differences are associated with disease. Tools provided by researchers such as Dr. Leonid Kruglyak are providing a head start.

Kruglyak, a UW associate professor of genetics and molecular biotechnology and an associate member of the Fred Hutchinson Cancer Research Center, applies his training as a physicist to population genetics so that he can develop computational methods for understanding variation in the human genome. He will discuss his work in a Science in Medicine Lecture, titled “Genetic Variation and Human Disease,” on Thursday, March 16, noon to 1 p.m. in T-625 of the Health Sciences Center.

The problem is daunting. Between any two unrelated individuals, geneticists estimate there are three million differences in DNA sequences, but that only one-tenth of these are actually dramatic enough to change the function of a gene. And only a small percentage of those, moreover, are dramatic enough to cause disease.

In the 1980s and 1990s, Kruglyak said, a majority of research was focused on identifying these dramatic genetic mutations and associating them with diseases such as breast cancer and cystic fibrosis. The usual approach to the problem is to study families with higher incidence of a certain disease over several generations to identify consistent mutations. The process requires many families and many years before a single dramatic mutation is identified.

Such “linkage analysis” cannot account for the fact that diseases such as heart disease are complex and likely involve interactions among numerous genes, as well as environmental factors. With the DNA sequences provided by the Human Genome Project, researchers are beginning to study large populations to determine which genetic variations really produce a higher incidence of diseases, such as Alzheimer’s.

The most common genetic variation is called single nucleotide polymorphism (SNP) - a single variation between the base pairs of different DNA samples. The entire human genome is a chain of approximately three billion base pairs.

So far, researchers around the country have identified more than 26,000 SNPs and logged them in a database hosted by the National Center for Biotechnology Information. Hundreds of thousands of differences will need to be identified before investigators can begin studying them in large populations and associating them with common complex diseases, Kruglyak said.

At the current rate at which SNPs are being identified, however, it may be possibile in five years for researchers to compare the genetic codes of large groups of healthy people and patients with heart disease, for instance. Such a study could lead to the identification of genetic variations responsible for risk factors such as high blood pressure, which would allow doctors to identify patients at risk for heart disease and provide early treatments.

Kruglyak received an M.A. in 1989 and a Ph.D. in physics in 1990 from the University of California, Berkeley. Prior to joining the UW and the Hutch, he was a research scientist at the Whitehead Institute for Biomedical Research in Cambridge, Mass., where he developed new methods for genetic analysis of traits with complex or polygenic inheritance.

In 1999, he was one of 10 young scientists worldwide to receive a $1 million research fellowship from the James S. McDonnell Foundation in St. Louis. ¶

Will Morton