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Structure Is the New SNP

  • Title: Senior Fellow, University of Washington
  • Education: PhD, University of Southampton, 2003
  • Recommended by: Evan Eichler

Move over, SNPs. Until recently, the main focus of clinically oriented genetics has been on single nucleotide changes and their connection to genetic diseases such as diabetes and obesity. But Andy Sharp says that's about to change. “Now that we're studying structural variation, we're realizing how much is out there, how variable one human is to another in terms of large rearrangements in their genome,” he says. “It's becoming clear that the structural variation in the human genome is probably just as, if not more important than, single nucleotide variation.”

Sharp, a member of Evan Eichler's lab at the University of Washington, expects that structural variation data will someday be routinely used in the clinical environment. “The more people are looking at the structural variation of the human genome, the more that we're appreciating that it's going to be involved in common human diseases,” he says.

His focus on structural variation and novel disorders in the human genome — “specifically recurrent ones,” says Sharp — has meant confronting challenges in studying the kinds of rearrangements he and his colleagues are interested in.

New types of studies require new techniques for analysis, and looking at structural variation is no different. One breakthrough came in the form of a pioneering technique called fosmid paired-end mapping, which Sharp feels is probably the best technique available for looking at structural variation across the entire genome. The method works by taking end sequences from high-density fosmid libraries, mapping them against a reference genome, and looking for discordances, Sharp says. “The power of that technique is that it can detect all types of rearrangements, including balanced rearrangements such as inversions, which the vast majority of other techniques can't,” he adds.

“It also enables you to then go in, fully sequence that individual rearrangement — which … most techniques don't allow you to do — so you get very high precision and very high sensitivity to all different types of things you're interested in,” he says.

Looking ahead

“Right now, we're kind of at a stage where we're trying to find out what in the human genome is there,” says Sharp. “It looks like maybe 5 percent of the genome is structurally variant in different individuals, so right now we’re  characterizing that, and trying to understand what type of variation is there and more importantly, what effect this might have on us as human beings.” Sharp and his colleagues are still very much in the initial stages of this characterization, but he predicts that in the near future, researchers will move from the current discovery phase to determining the influence of these changes in human phenotypes.

Publications of note

Sharp won the Student Award at a recent meeting of the American Society of Human Genetics for a study entitled “Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome” (published in Nature Genetics). The study describes the identification of several new genetic syndromes caused by the deletion of specific chromosomal regions that occur as a result of the architecture of the surrounding DNA.

Sharp's team investigated 130 regions that they believed to be possible candidates for undescribed genomic disorders based on the duplication architecture of the genome. The team tested 290 individuals with mental retardation using array comparative genomic hybridization. Their efforts demonstrated that sites of recurrent chromosomal rearrangement that cause genomic disorders could be successfully identified using an informed, duplication architecture-based approach. Sharp and his colleagues identified the deletion of a piece of chromosome 17q21.31, which appears to be the most common recurrent cause of mental retardation in humans.

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