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Visiting Student gets Close Look at Genetic Stroke Find

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Duke Health News 919-660-1306

What he didn't count on was being at ground zero for a thrilling discovery of an elusive gene that Marchuk and post-doctoral fellow Trilochan Sahoo had been seeking for two long years.

"It was very exciting to be able to participate in this research," said Jones, one of 10 undergraduate scholars who participated in Duke's Undergraduate Minority Summer Research Program. "I've gotten a lot of experience in the lab and had the opportunity to talk to several physicians and scientists about their work."

Jones, now president of his class, has always been interested in a medical career, but when his sister suddenly collapsed and died of an aneurysm on Dec. 30, 1997, that cinched his decision to become a neurosurgeon.

Jones' addition to Marchuk's genetics research team helped accelerate the search for a mutated gene that leads to an inherited form of bleeding strokes and seizures. The condition, called cerebral cavernous malformations (CCM), has been studied since the early 1970s, when a physician in Arizona first noticed that strokes and seizures ran in Mexican-American families in the area. People who have the disease develop one or more abnormal growths of blood vessels in the brain. Some people live with the disorder without ever developing symptoms, while others suffer excruciating headaches or seizures.

Several groups of scientists, including Marchuk and his collaborators, mapped the gene to a region on chromosome 7 and the search was on to find the gene. Marchuk convinced scientists working on the federal Human Genome Initiative to sequence this particular region of chromosome 7 as one of the first projects the group undertook. This provided the important raw data, the street map, of the area they needed to concentrate their search. But very few of the genes in the region had ever been named. It was like looking in the rainforest for an insect you've never seen among the many thousands of insects that have never been named or described before.

Marchuk and Sahoo decided to try to find the gene using sophisticated computer programs that search the raw gene sequence data looking for potential gene candidates.

"You have to remember," said Marchuk, "maybe 5 percent of the sequence in the region contains potential genes. We don't even know what the rest of the sequence is for."

The scientists had spent two years methodically marching through about 45 percent of the region, testing each gene they encountered against the DNA of 21 families whose members had CCM. By the time Jones joined the group in June, they still had not found the gene.

"Sahoo taught me how to use the computer programs, to pour and run sequencing gels, how to find the right sites to make primers for the sequencing, and what to look for in the gels," Jones said. He was a quick study and soon was planning and conducting experiments. One day, he found an irregularity in the sequence data that might indicate a mutation. The research team quickly compared the DNA sequence of the gene Jones had found to the DNA of five people whom they knew had CCM. Three of the five matched. Subsequent work showed that 16 of the 21 families they were studying had identical mutations in the gene. They had found their culprit.

"I told T.J. that this is what its all about," Marchuk said. "If you can't get excited about something like this, there's nothing that will excite you in science."

It turned out the gene was one of a handful of genes in the region of chromosome 7 that had previously been described. But very little is known about the gene.

Marchuk and Sahoo are publishing their findings in the November issue of the journal, Human Molecular Genetics, but the study findings were released earlier this month when a French team reported finding the same gene. The effort to identify the gene, which the Duke team calls "KRIT1," had been a race among several groups of researchers. Even though other researchers call the candidate gene something else, "the name of the gene hardly matters because so little is known about it," Marchuk said.

"If you had asked me before to speculate that this was the gene, I wouldn't have guessed this one. It wasn't obvious," Marchuk added. "That's the power of the new gene identification programs. You can narrow down your search without having to blindly guess or use cumbersome biochemical methods to find genes."

Marchuk said the importance of finding the gene is that it is one of the first to address genetic risk factors for a relatively common disease: stroke.

"Looking for risk factors for common diseases is going to be tricky," he said. "Our idea is to start with genes for inherited forms of disease that affect many members of a family, try to learn about them first, and then use that information to broaden the search to heart disease and other common disorders."

Jones said the discovery had added meaning for him because he is contributing to understanding why people suddenly have bleeding in the brain, the very condition that killed his sister two years ago.

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