UW News

October 16, 2000

Grant allows researchers to study genetic variations in the human genome

A $10 million grant will allow researchers at the University of Washington and the Fred Hutchinson Cancer Research Center to conduct an unprecedented study of genetic variation and how it may affect the function of human genes — and, ultimately, our susceptibility or resistance to disease.

The grant, awarded over four years, is from the National Heart, Lung, and Blood Institute (NHLBI), one of the National Institutes of Health. It is one of 11 new Programs for Genomic Applications, which the NHLBI is funding to apply and expand upon the data generated by the Human Genome Project. The goal is to gain new insights into common human diseases such as high blood pressure, heart disease, stroke, asthma and chronic lung diseases like emphysema.

The Human Genome Project has so far identified the roughly 3 billion nucleotides, or building blocks, of DNA present in each cell of the human body. These nucleotides carry the instructions for human life and function. The human genome sequence is just the beginning of what researchers want to learn. Researchers now want to decode more about the structure and function of human DNA and its role in the function of the heart, lungs, and blood. In order to reach that goal, researchers want to know how your DNA differs from someone else’s.

Most of the genome is identical from person to person — perhaps 999 out of every 1,000 nucleotides are the same. But there are differences, which scientists call “single nucleotide polymorphisms,” or SNPs (pronounced ‘snips’) for short.

“People basically have the same sequence. However, there are small differences. We want to know what this means to human function and our susceptibility and resistance to disease,” said Dr. Deborah Nickerson, director of the program and an associate professor of molecular biotechnology in the UW School of Medicine. “We are just starting to learn more about variation (or differences) in the human genome.”

Dr. Leonid Kruglyak and his group at the Hutchinson’s Human Biology Division play a key role in the new project and will help to determine which of the hundreds of SNPs are important for further testing of the potential links between disease susceptibility and resistance, and common human diseases, Nickerson said.

We already know that genetic differences help determine such characteristics as height and eye color. And we know that rare inherited differences can cause diseases like Huntington’s disease, cystic fibrosis and sickle cell anemia. What’s not known is how more commonly inherited differences might be involved in the development of more common problems such as heart disease, asthma, emphysema or high blood pressure.

The UW-Hutchinson Center project will seek the common genetic variations that occur in the inherited DNA code that governs an important body process: inflammation. Inflammation is the response to damage such as trauma or exposure to chemicals and infection. Inflammatory responses in the body are suspected in heart disease and stroke, and are known to be involved in many lung diseases like asthma or emphysema.

“Differences in inflammation could underlie a lot of common problems,” Nickerson said.

What makes the question even more complicated is that genes do not do the actual work in inflammation; they produce proteins that do that work. There are hundreds of proteins involved in inflammation, Nickerson said. So researchers will be studying differences among 50 people to find the common variations in hundreds of proteins. And as if that was not complex enough, those 50 people will have a genetic code with a hundred or so variations each.

To analyze these massive data sets, Nickerson uses a program that she and UW colleagues have developed, called PolyPhred, that identifies SNPs. PolyPhred works with Phred, a program that was developed by Dr. Philip Green, a UW professor of molecular biotechnology and adjunct faculty in computer science. Phred is used worldwide to handle the data generated by the Human Genome Project and related investigations. The newly funded UW-Hutchinson program will allow researchers to determine the most common variations in human DNA. They will build evolutionary trees to determine the history of inheritance of these SNPs, using programs like Phylip developed by <a href="http://depts.washington.edu/genetics/faculty/felsenstein.html"!
>Dr. Joe Felsenstein, a UW professor in the Department of Genetics.

Like the Human Genome Project, all data produced by this new group will be made publicly available to benefit research throughout the world, Nickerson said.