Science: The Gene Hunt

Scientists launch a $3 billion project to map the chromosomes and decipher the complete instructions for making a human being

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Finding the location of a gene on a chromosome is even more complicated. But over the past several years, scientists have managed to draw rough maps of all the chromosomes. They determine the approximate site of the genes, including many associated with hereditary diseases, by studying patterns of inheritance in families and chopping up their DNA strands for analysis. With this technique, they have tracked down the gene for cystic fibrosis in the midsection of chromosome 7, the gene for a rare form of colon cancer midway along the long arm of chromosome 5, and the one for familial Alzheimer's disease on the long arm of chromosome 21.

One of the more dramatic hunts for a disease gene was led by Nancy Wexler, a neuropsychologist at Columbia University and president of the Hereditary Disease Foundation. Wexler was highly motivated; her mother died of Huntington's disease, a debilitating and painful disorder that usually strikes adults between the ages of 35 and 45 and is invariably fatal. This meant that Wexler had a 50% chance of inheriting the gene from her mother and contracting the disease.

In a search coordinated by Wexler's foundation, geneticist James Gusella of Massachusetts General Hospital discovered a particular piece of DNA, called a genetic marker, that seemed to be present in people suffering from Huntington's disease. His evidence suggested that the marker must be near the Huntington's disease gene on the same chromosome, but he needed a larger sample to confirm his findings. This was provided by Wexler, who had previously traveled to Venezuela to chart the family tree of a clan of some 5,000 people, all of them descendants of a woman who died of Huntington's $ disease a century ago. Working with DNA samples from affected family members, Gusella and Wexler in 1983 concluded that they had indeed found a Huntington's marker, which was located near one end of chromosome 4.

That paved the way for a Huntington's gene test, which is now available. The actual gene has not yet been isolated and since there is no cure at present, many people at risk for Huntington's are reluctant to take it. "Before the test," Wexler says, "you can always say, 'Well, it can't happen to me.' After the test, if it is positive, you can't say that anymore." Has Wexler, 43, taken the test? "People need to have some privacy," she answers.

Tracking down the location of a gene requires tedious analysis. But it is sheer adventure when compared with the task of determining the sequence of base pairs in a DNA chain. Small groups of scientists, working literally by hand, have spent years simply trying to sequence a single gene. This hands-on method of sequencing costs as much as a dollar per base pair, and deciphering the entire genome by this method might take centuries.

The solution is automation. "It will improve accuracy," says Stanford's Paul Berg. "It will remove boredom; it will accomplish what we want in the end." The drive for automation has already begun; a machine designed by Caltech biologist Leroy Hood can now sequence 16,000 base pairs a day. But Hood, a member of the Genome Advisory Committee, is hardly satisfied. "Before we can seriously take on the genome initiative," he says, "we will want to do 100,000 to a million a day." The cost, he hopes, will eventually drop to a penny per base pair.

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