About this same time, at Toronto's Hospital for Sick Children, Scherer was equally puzzled by what he was seeing in the genome. He and his colleagues were searching chromosome 7 to uncover genes involved in disease. In the process, they were uncovering massive and unexpected differences in the chromosomes of different people. "Most geneticists thought that if you had a large genetic change, it would be associated with disease all the time," says Scherer. But he and his team were finding big differences that didn't seem to have an obvious effect on health—including million-base-pair insertions or deletions, "which was really unbelievable."

Many geneticists were skeptical. At that time, the technologies they were using were so new that the differences might have come from experimental design or malfunctioning equipment. "We were criticized a lot," Scherer says. "My first grant application [to study structural variation] was rejected, because people said it couldn't possibly be true."

But as analytic techniques improved, so did the evidence for substantial structural variation. Charles Lee of Brigham and Women's Hospital in Boston had found similar DNA differences, as had a group at Cold Spring Harbor Laboratory led by Michael H. Wigler. By about 2003, the case for widespread structural variation in the human genome was becoming unassailable.

Furthermore, evidence was accumulating that some of these variants influence health. The human genome regulates itself through a process still largely unknown. But variable numbers of a gene can produce a greater or smaller amount of a protein important to the body, and a duplicated section of DNA can disrupt the function of an important gene.

As Scherer and others investigated the genomes of people with genetic disorders, they found that structural variation often seemed a more likely contributor to the disorder than DNA spelling differences. Schizophrenia, Alzheimer's, Parkinson's, autism, kidney disease, and many other diseases were linked to structural variation. "We've been shocked to see how quickly the idea has been adopted and how many diseases are being associated with large structural variants," Scherer says.

In the past couple of years, Scherer has focused on structural variants in patients with birth defects and neurological disorders. For example, at the Hospital for Sick Children screens of children with unexplained genetic disorders have shown that some 20 percent have structural changes in their DNA that may contribute to their conditions. He also has been participating in studies to identify and characterize structural variation in the genome, including differences between chromosomes in the same cell (see "A True Individual," page 5). "It's incredible how many people are using these data, from commercial companies to clinical geneticists to everyone in between," he says.

At the University of Washington, where he moved in 2004, Eichler and his colleagues also have been delving into the link between structural variation and disease. In one particularly intriguing study, they examined the DNA of 290 British children with neurological disabilities. "We were looking for recurrent deletions in regions of the genome that are highly dynamic," says Andrew Sharp, the postdoctoral fellow in Eichler's lab who headed the project.

Of the 290 children, 16 had deletions or duplications that are "likely to be pathogenic," according to the group's September 2006 paper in Nature Genetics. Remarkably, four had very similar but not identical deletions on the long arm of chromosome 17. All four, though unrelated, had very similar features, including silvery hair, blue eyes, and a bulbous nose—"they could be brothers and sisters," says Sharp—but their shared characteristics hadn't been noticed before. And the region of their deletions included several genes implicated previously in neurological and behavioral conditions.

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