The one percent solution

Roche's 454 Life Sciences and SeqWright bring their technologies to bear on the human exome to help understand dilated cardiomyopathy

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BASEL, Switzerland—Roche Applied Science and its 454 Life Science center of excellence are teaming up with Houston, Texas-based SeqWright and the University of Miami Miller School of Medicine in a collaboration aimed at using complete sequencing of the coding portion of the human genome to help elucidate the underlying genetic causes of heart disease.

This collaborative research effort is focused on identifying possible genetic variants associated specifically with dilated cardiomyopathy, and in this collaboration SeqWright is using NimbleGen Sequence Capture Human Exome Arrays to enrich more than 180,000 exons from DNA samples from individuals affected with this particular heart disease.

Using the Genome Sequencer FLX technology available from 454 Life Sciences, SeqWright is sequencing the enriched exons to detect genetic variants within genetic samples, including single nucleotide polymorphisms (SNPs) and insertions and deletions. This particular technology is being used because Roche's technology is a "complete solution" that allows targeted resequencing of all of the coding exons—the human exome—the portion of the human genome that is transcribed and translated into the various proteins that carry out the functions of the cells in the body, according to Dr. Fei Lu, CEO of SeqWright, a custom genomic and molecular biology services company.

"Sequencing the entire coding portion of the human genome has not been feasible until recent advancements in next-generation genomic tools," Lu notes. "By being able to efficiently characterize the entire human exome, researchers can accelerate their research by taking the 'candidate gene' approach to a completely new level. It's truly amazing to see just how fast research has transformed with these tools and I'm proud to see that SeqWright has stayed ahead of the community as we adopt these technologies almost as fast as they are developed."

The approach of resequencing only the coding portion of the human genome is an approach with both great advantages as well as limitations, both for this study and for future research work that may take a similar tack, notes Tim Harkins, director of marketing, Roche-454.

"The coding region is one one-hundredth of the human genome, so the management of the data itself is much easier than with a whole-genome approach and there are great costs benefits in terms of both resources and time," Harkins says. "The coding regions are clearly an important part of genomics but at the same time, so is the other 99 percent of the human genome, so researchers have to take care to remember that something like this isn't the end-all of genomics. But it does offer a chance to get a much more in-depth knowledge of disease than has been previously possible, since sequencing the whole genome is definitely not for the faint of heart."

Looking beyond the issue of dilated cardiomyopathy, Harkins says that this approach of focusing on coding exons will probably be most powerful in research related to cancer and to Mendelian diseases—those diseases strongly related to hereditary genetic inheritance. Harkins says that Roche has several other collaborations underway to research those areas, though he didn't confirm whether SeqWright will be tapped for other disease areas as well. For this collaboration on dilated cardiomyopathy, Harkins did note that Roche was attracted to SeqWright's extensive contacts with the clinical research community, its position "on the bubble" of translational research, and the combination of "great data quality and great turnaround" that it offered.

As to why the focus on this particular disease right now: "Dilated cardiomyopathy is a leading cause of heart failure that carries a high mortality rate," says Dr. Nadine Norton, a research assistant professor from the University of Miami Miller School of Medicine.

"We know that familial dilated cardiomyopathy can be explained by mutations in more than 20 autosomal and two X-linked genes, yet mutations in these genes account for only one-third of the cause. By using an experimental strategy that employs the sequencing of all coding regions within the human genome, we hope to identify other mutations in other genes that cause this terrible disease."

This work is part of an ongoing 15-year study of familial dilated cardiomyopathy brought to the Miller School of Medicine in 2007 by Dr. Ray Hershberger, professor of medicine and associate chief of the school's Cardiovascular Division.

In other SeqWright news announced mere days after the Roche collaboration, the company noted that Cambridge, Mass.-based personal genomics company Knome will be offering its personal genome sequencing and analysis service through SeqWright's CLIA-certified laboratory. Under the agreement, SeqWright plans to process and sequence customer samples using Applied Biosystems' SOLiD and Roche 454 sequencing platforms, while Knome will analyze and interpret the genetic data.
Knome currently has two sequencing and analysis options for its customers. The first KnomeSELECT includes exome sequencing and customized analysis.

KnomeCOMPLETE, meanwhile, involves whole genome sequencing and analysis, including trait and disease associations.

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