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Structural variation New NHGRI direction follows copy number variation trend


Type “copy number variation” into Google and the search engine pulls up close to 43 million hits. The breathless popularity gain seen in this field surprises even pioneers like Evan Eichler, who remembers when most scientists thought the concept of quantifying copies of genes and using that information to compare one genome to another was purely “an idiosyncrasy of the genome.” He adds, “The people that are now extremely excited about it — they weren’t so excited by it 10 years ago” when he was beginning to study it.

Copy number variation, which along with insertions and deletions falls under the broader umbrella of structural variation, has truly come into its own. Recent papers have linked the phenomenon to kidney disease, AIDS susceptibility, Alzheimer’s, and Parkinson’s. With each new connection between phenotype and genome sequence change, it seems, even more people flood into the field. Earlier this year, NHGRI issued its priorities for the production-scale genome centers, and topping the list was an initiative to study structural variation in 48 human genomes.

Steve Scherer, director of the Centre for Applied Genomics at the Hospital for Sick Children, was one of the organizers of the first copy number variation meeting held last September in his home base of Toronto. “It was quite timely because there had not been a meeting really on this at all because it’s such new science,” he says. About 60 participants came, and the meeting was such a hit that it will actually merge with the annual SNP conference; the first co-meeting will be held in Hong Kong this September.

For most people, copy number variation research has a fairly brief history. The first papers describing this on a genome-wide scale came out in 2004 — one from Mike Wigler’s lab at Cold Spring Harbor and another from Scherer and Charles Lee at Harvard. That was the first time, Scherer says, that the technology was available to study this in a large-scale, rigorous manner. “We knew about it for a long time, we just didn’t have the technology to prove it,” he says. “We started to look genome-wide in 2002 when array CGH became more available to us.”

Most copy number variation research relies on BAC- or oligo-based arrays, but those don’t show broader structural variation events like insertions and deletions, says Eichler. Sequencing technology, on the other hand, gives more comprehensive information but for many researchers is prohibitively expensive.

Scherer says a genome-wide scan can be done with current array technology for $1,000, but he adds, “If we could bring it down 10-fold, it brings it into the realm of the average laboratory experiment” — which will likely be necessary to get this technology into the hands of clinical scientists.

Scherer has also been an organizer of a consortium that aims to analyze samples from the HapMap project for their copy number variation content. “We’ve been working on that for a year and a half now,” he says. “We’ll be preparing our data for publication this year sometime.” Going forward, Scherer hopes the consortium will look at more samples from a broader global population and do more disease-association studies too.

Both Eichler and Scherer point to the need for improved database work in the field. Scherer says there should be a common repository that allows scientists to compare all of the data in this area, while Eichler says developing a quality control system — preferably one in which data is vetted and distributed by people other than those who generated it — will be key. They look forward to improvements in the variation detection technology as well. “The technology is there,” Scherer says, “but it’s there in a rudimentary form.”

Looking ahead, Scherer says, “the ultimate success story would be if in the next [few] years every single genetic disease study incorporated a component of copy number variation or structural variation in their experiment design.”

Eichler’s view of the field in a couple of years is a little less rosy. “There’s a lot of excitement and there should be a lot of excitement, but right now we might be a little over the top,” he cautions. “Two years from now there’ll be a little bit of after-the-party blues.”

— Meredith Salisbury

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