DNA Duplications and Deletions Help Determine Health

Each human's genome is distinguished by extra, and sometimes missing, DNA that can powerfully impact everything from development to disease

In 1991, both Science and Nature turned down James Lupski's submission that described an unprecedented link between an inherited human disease and a novel chromosome aberration. "It was rejected without even being sent out for review," recalls Lupski, a geneticist at Baylor College of Medicine in Houston, Texas. Unlike the many studies that fingered tiny mutations in genes as the cause of inherited diseases, Lupski pointed to a relatively large, duplicated region of one chromosome as the culprit. Later research showed that this duplication, inserted within the same chromosome, harbors an additional copy of a gene involved in making a nerve cell's protective sheath. The extra dose of the gene caused the sheaths to disintegrate, interrupting signals between the brain and the hands and feet. At the time, "there was no appreciation that copy number was a mechanism of disease," says Lupski, whose study appeared in Cell later that year.

Lupski's link between gene copy number and the peripheral neuropathy known as Charcot-Marie-Tooth disease (CMT) marked the opening of a new chapter in human genetics. Not only has his discovery led to progress in understanding and potentially treating this devastating disease, but it also set the stage for what has recently become a frenzy to find other connections between disease and gene duplications or deletions. As new techniques to spot such genetic differences have become available, investigations of the human genome have found thousands of variations in the number of copies of a gene, a piece of a gene, or large stretches of DNA--so-called copy number variants, or CNVs. "This whole new world has been opened up in genetic variation," says cytogeneticist Charles Lee of Brigham and Women's Hospital in Boston.

Geneticists are steadily linking more and more of these CNVs to human maladies, including Alzheimer's, Parkinson's, various mental retardations, autism, color blindness, and anatomical deformities. Several studies have shown that CNVs can also powerfully influence a person's susceptibility to disease and to the side effects of medications. And each connection between a CNV and a disease suggests novel targets for therapies.

CNVs have become such hot commodities that some researchers now contend they're as important as mutations in genes themselves. And several companies that specialize in analyzing DNA have developed new tests to detect CNVs. "We're starting to see CNVs incorporated into most genetic studies now," says Stephen Scherer, a medical geneticist at The Hospital for Sick Children in Toronto, Canada.

But with all the excitement surrounding CNVs, several leading researchers in the field urge colleagues to keep their enthusiasm in check. One caveat is that the main technologies used to pick out duplications and deletions are relatively blunt tools, leading to widespread concern that far more CNVs have been reported than truly exist. "There's a lot of hype in the CNV field right now," says Lee.

Yet there's growing agreement that CNVs can have a profound influence on determining what makes individuals unique, reaching far beyond health status to affecting underlying differences in looks and personalities. "What's cool is that we're a mosaic of pieces of genomes," says Evan Eichler, who studies gene duplications at the University of Washington, Seattle. "None of us is truly normal."