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Geneticists like Evan Eichler (left) and Stephen Scherer (right) are tying structural variation seen in our genomes to an increasing number of diseases.
"The human genome" is a misnomer, according to Eichler. G248 has big sections of DNA that other people don't have, and she's missing DNA that most people do have. "In the last few years, it's been shown that big changes in DNA—insertions and duplications and deletions and inversions—are extremely common in the population," Eichler says. "That's the first important point. The second important point is that these changes play a role in human disease—everything from HIV susceptibility to autism to mental retardation to epilepsy."
A few years ago, most human geneticists would have been very skeptical about such a statement. At that time, geneticists focused almost exclusively on spelling differences in the human genome—places where the chemical bases that make up DNA, represented by the letters A, T, C, and G, differ from one person to another. According to the thinking of the day, these individual changes in DNA codes largely accounted for differences in our genetic susceptibility to disease and in our physical appearance.
But in the first half of this decade, a handful of geneticists, working independently at laboratories scattered across the United States and Canada, began to notice something strange. As they looked more carefully at human DNA, they found that some people had multiple copies of big sections of DNA, hundreds or thousands of base pairs long. Sometimes these structural variants, as they came to be known, were in DNA regions that didn't seem to be doing anything. But sometimes they were in regions rich with genes, so that some people had more copies of particular genes than other people.
"We were finding a huge amount of copy number variation—that was the message," says another pioneer in the study of structural variation, Stephen W. Scherer, a former HHMI international research scholar who directs the Centre for Applied Genomics at the Hospital for Sick Children in Toronto, Canada.
The discovery has been a revelation for many geneticists. "A lot of the more complex disorders are not explained by coding variation, which is what people were looking for," says HHMI investigator Val C. Sheffield, who for years has suspected that structural variation might play a prominent role in the eye diseases he studies in his University of Iowa lab. "But until recently we haven't had the technologies to look at variation on a genome-wide scale."
The new picture that Eichler, Scherer, and a handful of other geneticists have been painting differs radically from the traditional view of our genome. Instead of the book of life, DNA is more like the scrapbook of life. Sentences, paragraphs, or entire chapters are copied and haphazardly inserted into various parts of our genome. In some people, the same page repeats over and over, while other people don't have that page at all. And geneticists have been tying this structural variation to an increasing number of diseases. "It's amazing," says Scherer. "At human genetics meetings, 30 to 40 percent of the talks have a direct focus on copy number variation."
The discovery of structural variation was partly a consequence of better technologies and new data. But it was also a case, says Eichler, of "good luck favoring the prepared mind."
Photos: Eichler: Ron Wurzer / AP, © HHMI, Scherer: Evan Dion