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NHLBI, NHGRI Offer $12M to Cut Cost of Exon Sequencing for Large-Scale Disease Studies

Release Date: January 29, 2008

Publication: In Sequence: The Inside Read on Genome Sequencing, Vol. 2, No.5

Author: Julia Karow

The National Heart, Lung, and Blood Institute and the National Human Genome Research Institute have set aside $12 million in grants to help reduce at least tenfold the cost of whole-genome exon sequencing methods and enable future genome-wide exon resequencing studies that will focus on specific diseases.

The new technology grant program, which plans to make up to four awards this fall totaling $12 million over two years, as well as disease studies NHLBI has planned for the future, complement the 1,000 Genomes Project that the NHGRI, the Wellcome Trust Sanger Institute, and the Beijing Genomics Institute announced last week.

Unlike that project, which aims to catalog genetic variations in human populations unbiased for disease, the resequencing technology program is geared towards studies that will correlate sequence variations with disease phenotypes.

“We built a consensus, through informal and some formal meetings we convened, that the time was right to take the next-generation technologies that are being developed and implemented and build the kind of pipeline that would be required for large-scale production sequencing” of thousands of samples from disease-specific collections maintained by NHLBI, Alan Michelson, associate director for basic research at NHLBI, told In Sequence earlier this month.

The goal is to develop inexpensive methods for capturing and sequencing all exons, which make up between 1 percent and 2 percent of the human genome. Other functional regions, such as microRNAs and regulatory elements, might also be included, according to the grant announcement.

These methods would fill a technical void for studies that neither seek to resequence entire genomes nor to resequence a single candidate gene, according to Weiniu Gan, a program director in the genetics, genomics, and advanced technologies program of the division of lung diseases at NHLBI.

“We think this is a gap [and] we want to see if we can fill that,” he said.

Exon Marks the Spot

At the moment, sequencing an individual’s exome, or about 60 megabases of DNA, at high quality — including all costs such as personnel, reagents, instrument amortization, and facilities — costs “multiple tens of thousands of dollars,” according to Adam Felsenfeld, program director of the large-scale sequencing program at NHGRI. “Right now, that’s too expensive to do routinely,” he said. The aim of the program is to reduce this cost to about $1,000 per sample.

To reach this goal, researchers awarded the two-year grants will combine new technologies and methods for sample preparation, target capture, sequencing, and data management and analysis into an “integrated re-sequencing pipeline,” according to the grant solicitation.

According to Felsenfeld, developing new capture methods and integrating them with different sequencing platforms will be among the main technical challenges researchers need to overcome.

“Although there are some very encouraging capture methods, I think the field is not settled yet,” he said. “There are some early successes, but I think there is a long way to go and a lot of opportunity out there.”

Last year, several research groups published studies that coupled new DNA capture methods with new sequencing technologies, such as NimbleGen microarrays with 454’s sequencer, NimbleGen arrays with Illumina’s Genome Analyzer, and an Agilent oligo-based PCR-like approach with Illumina’s sequencer (see In Sequence 11/6/2007).

But these will likely not remain the only methods for exon sequencing. “Things won’t settle for some time because new and better techniques are going to constantly be dropped into the mix for some time, and people are going to look at those in combination with their other technologies and see what’s best,” Felsenfeld said. He added that several successful combinations of capture and sequencing might emerge in the end.

According to the funding announcement, the research will probably take place in two phases. During an initial “optimization phase,” scientists will develop and fine-tune their methods and put them into a production pipeline using DNA samples that have already been characterized in genome-wide genotyping or sequencing studies, such as the HapMap samples, which are unbiased for disease. Fewer than 20 DNA samples per investigator “may be sufficient” for this phase of the project.

In the second, scale-up phase, scientists will run hundreds of DNA samples to see if their re-sequencing pipeline is suitable for sequencing all exons in thousands of DNA samples in later studies.

Technologies developed under the NHLBI/NHGRI’s program might also benefit the 1,000 Genomes Project. Under one of its pilot projects, participating sequencing centers will sequence exons of about 1,000 genes in about 1,000 individuals.

Last week, Elaine Mardis, co-director of the Genome Sequencing Center at Washington University, told In Sequence that her center has not yet decided which capture method to use in that pilot study, but it will consider both an in-house method and approaches based on Agilent and NimbleGen technology (In Sequence 1/22/2008).

Date Posted: February 2, 2008

Last Updated January 2011

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