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Until recently, only limited efforts had been made to search for rare variants linked to common diseases. This search may involve sifting through every letter of DNA–something that can only be done by sequencing. With the old technology, that was too expensive to be practical. But in view of the disappointing results from microarray studies, scientists are turning to the fast new sequencing technologies to rigorously test the rare-variant hypothesis. It’s likely that “much of the rest of the heritability [of disease] is hiding in rare variants with high impact,” Collins says. “If we really want to understand the genomics of disease, we need complete genome sequences.”

It’s still unclear how much rare variations contribute to disease, but evidence is starting to trickle in. In a study published this summer, biologists at the University of California, Berkeley, sequenced the gene for an enzyme called MTHFR, which converts the B vitamin folate (folic acid) from one form into another. Scientists had previously identified a common genetic variant that produces a weakened version of the enzyme, increasing the risk of birth defects and possibly of heart disease. By sequencing the MTHFR gene in 564 people of different ethnicities, Nick Marini and colleagues found four new variants that also impair the enzyme’s function; present in fewer than 1 percent of the subjects, these variants would have been undetectable in microarray studies.

The Personal Genome
At a recent conference at the venerable Cold Spring Harbor Laboratory on Long Island, James Watson, codiscoverer of the structure of DNA, sat slouched in the front row of the auditorium beneath a large portrait of himself. Watson, who for a time headed the Human Genome Project, had his genome sequenced in 2007. His was only the second individual genome to be completely mapped. (Craig Venter, who led the private effort to sequence the genome, used his own DNA as the sample.)

Watson isn’t known for sitting through successive conference presentations. But a good portion of this conference was about him. He attended talk after talk, as scientists presented their analy­ses of what has become affectionately known as “Project Jim.” ­Watson is a seemingly healthy 80-year-old man, and the results of scrutinizing his genome have so far been fairly mundane. He has extra copies of genetic variations shown in previous studies to protect against heart disease and macular degeneration, for example. An initially worrying mutation in the BRCA1 gene, which is linked to breast cancer, turned out to be harmless. But the vast majority of Watson’s genome remains uninterpretable. Scientists have yet to find a genetic component to his intelligence or his curiosity or his tendency toward politically incorrect outbursts. Perhaps most important to Watson, it’s not yet clear whether he harbors a genetic vulnerability to schizophrenia that he passed along to his son, who has the disease.

The Human Genome Project’s reference sequence, which is a composite of genetic information from more than 20 individuals, gave scientists a basic blueprint of the genome. But a single genome has its limits. It’s only by comparing multiple genomes that scientists can begin to get a handle on the genetic variability that underlies the vulnerability to disease or madness, the tendency to athletic prowess or mathematical genius, the drive toward altruism or aggression.

Even Watson, who has spent his career trying to understand DNA, seems less than impressed to see the details of his genome presented. “We’ll see if any of it adds five minutes to my life span,” he remarked at the conference. Indeed, the meaning of most of his genetic quirks will remain a mystery until many more people join him in having their genomes sequenced.

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Credits: Justin Fantl, courtesy of personalgenomes.org
Video by Conrad Warre

Tagged: Biomedicine, Pacific Biosciences

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