The Holes in Our Genomes

Scanning DNA for structural changes brings new insight into disease.

Over the past two years, scientists have made a surprising discovery about our DNA. Like a book with torn pages, duplicate chapters, or upside-down paragraphs, everyone's genome is riddled with large mistakes. These "copy number variations" can include deletions, duplications, and rearrangements of stretches of DNA ranging in size from one thousand to one million base pairs. New tools to screen for such mistakes, described this month in Nature Genetics, should generate a more complete picture of the genetic root of common diseases.

Hole-y DNA: Gene microarrays (shown above) designed to measure two different kinds of genetic variation--single-base changes and larger structural variations--are shedding new light on the genetic basis of complex disease. Credit: Broad Institute

"There has been a shock at the prevalence of this kind of variation and a desire to characterize it more fully and to integrate it into genome-wide studies of disease," says Matthew Hurles, a geneticist at the Wellcome Trust Sanger Institute, in Cambridge, U.K., who was not involved in either study. "Now we have the tools that will enable those discoveries."

Over the past few years, advances in gene microarray technologies, which can quickly survey large volumes of DNA, have allowed scientists to screen more human genomes than ever before, resulting in a flood of information linking specific genes to disease. Most of these studies begin by looking for single-letter changes in the DNA code, called single-nucleotide polymorphisms, or SNPs (pronounced "snips"). SNPs found more often in people with a particular disease point researchers to genetic variations that might play a role in that disease. Scientists have so far identified 200 disease-linked genes using this approach, but even large studies of thousands of patients have uncovered genetic variations that account for only a small proportion of complex diseases. In type 2 diabetes, for example, the 18 disease-linked genes that have been identified explain perhaps 5 percent of the disease's heritability.

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Scientists have now adapted these microarrays to identify both small SNP changes and copy number variations, which they hope will help them identify a larger fraction of disease-causing genes. In one of the papers in Nature Genetics, David Altshuler, a physician and scientist at the Broad Institute, in Cambridge, MA, and his collaborators described the design of such a chip, in collaboration with genomics instrument maker Affymetrix, which they then used to map this kind of variation.

Altshuler's team assayed the DNA of 270 people whose genomes were already being studied as part of the HapMap project, which is cataloguing common genetic variants. They found that most copy number variations are inherited, as SNPs are, rather than arising anew in individuals. That news is likely to be a relief to geneticists, because it means that they can survey many structural changes by employing the same high-throughput approach used to catalogue SNPs.