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In the early 1980s, researchers turned to large extended families and a technology known as linkage analysis to begin systematically searching for disease-carrying genes. By following the pattern of disease inheritance in large families and linking the presence of the disease to known genetic markers-long regions, for instance, in which the DNA letters A and C alternate repeatedly-geneticists could first localize the disease-causing gene to a specific chromosome or specific chromosomal region. They would then employ a technique called positional cloning to scour the nearby DNA for the genes and finally identify a particular misspelling that led to disease. The techniques were developed in “a spectacular series of discoveries,” says MIT geneticist David Altshuler.

But success didn’t come easy. Nancy Wexler, for instance, started her search for Huntington’s in 1979. By 1983, using blood samples sent from Venezuela, her colleague James Gusella of the Harvard Medical School had narrowed the position of the Huntington’s gene to a short tip of chromosome four that was only a million base pairs in length. It took another 10 years to identify the gene at work and nail down the critical mutation.

Since then, geneticists have identified hundreds of disease-causing genes, using ever faster methods of testing DNA samples, ever faster computers and a new generation of software to compare and contrast DNA variations. The sole caveat in this remarkable accomplishment is that virtually every gene identified, with a few exceptions, has been for a disease caused by a single gene and a single mutation. These are rare diseases-like Huntington’s or cystic fibrosis-because evolution strongly selects against them. When geneticists used the same techniques to look for the genetic causes of common chronic diseases like heart disease and cancer, success was considerably harder to come by.

That these common diseases have a degree of “heritability” is undeniable. But the last decade of mostly negative studies is compelling evidence that the underlying genetics is indeed complex. It may be the interaction of two or three genes and gene variants that predisposes an individual to a specific chronic disease. It may be considerably more-each having a minor effect on the likelihood of contracting the disease or the eventual outcome.

This complexity makes the search for chronic-disease genes extremely difficult. If the impact of any one gene is so small-say five percent as opposed to the 100 percent of the Huntington’s gene-then following the connection through the black box becomes that much more difficult amidst the noise of environmental factors and other genes. “You might be looking for a combination of three or 10 or 100 genes,” explains Altshuler, “each of which might have multiple mutations in it that might affect the disease, and all of them collaborating with the environment and perhaps randomness or fate. So the correlations will be much, much weaker. It means you need different tools to augment the search. In particular, it means you have to look at lots of people. Imagine if one gene causes the disease; you might look at as few as five or 10 families, each with lots of people, and be able to pick out the correlation. The numbers don’t have to be that large to make a compelling case. If no single gene or mutation is going to explain more than five or 10 percent of the disease, you need hundreds or thousands of people.”

Indeed, solving the puzzle would probably be impossible if not for the recent advances in the computer and lab technologies used to determine the genotypes of individuals. In addition, the Human Genome Project now provides a map of the entire three billion base pairs that constitute the human genome. “A necessary step,” says Altshuler, “is to know what the genes are and have very fast and efficient tools for finding variations and asking, does this variation correlate with a disease? Now the Human Genome Project provides a list of all the genes, and that is fundamentally empowering. Even in the previous paradigm, where the disease, like Huntington’s, was caused by a single gene of big impact, you had to find all the genes in the local region, characterize them and figure out which one has the variation. That would take an army of people. The Human Genome Project has come along and done a lot of that labor up front.”

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Tagged: Biomedicine

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