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NHGRI Plots New Course for Sequencing Centers

By Matt Jones

NEW YORK (GenomeWeb News) – The National Human Genome Research Institute is planning to change its Large-Scale Sequencing Program to include funding for a new Center for Mendelian Disorders, clinical sequencing centers, and a program to boost the institute's genomic data analysis capacities, in addition to its continued support for genomic sequencing centers.

The sequencing program, which is up for renewal in 2011, will use the bulk of its resources for the Large-Scale Genome Sequencing and Analysis Centers, but it also will evolve with the addition of the new points of focus that are aimed at addressing a changing molecular biology research and business environment.

The new plans for the sequencing program were approved at an NHGRI policy meeting in mid-May, and the institute's staff now plans to start writing requests for applications to fund these programs. It plans to issue RFAs in the fall.

NHGRI expects that the new large-scale program will cost around the same as it does now — around $110 million per year — with around $90 million of that going to fund the centers for sequencing projects, and the remainder being used for the new projects.

The current NHGRI Large-Scale Sequencing Research Network is made up of three sequencing centers, including the Broad Sequencing Platform at the Broad Institute of Harvard and MIT; the Human Genome Sequencing Center at Baylor College of Medicine; and The Genome Center at Washington University School of Medicine, St. Louis.

"This is a framework for what elements the future program will include," Adam Felsenfeld, NHGRI's program director for the Large-Scale program, said in a statement. "Although there are still many conversations and decisions that need to occur internally before we issue the request for applications, the main point is that we will continue our successful large-scale sequencing program."

In an interview with GenomeWeb Daily News, Felsenfeld said that he sees some larger trends that have affected NHGRI's needs and have led to the shift to Mendelian diseases, bioinformatics, and clinical applications.

"One of these is that sequencing, especially very large-scale sequencing, continues to push towards understanding complex diseases, and in general to understand disease. Another is that it is less and less possible to divorce the production of sequence from its analysis and what it is to be used for," he said.

According to the NHGRI proposal, the Large-Scale Genome Sequence and Analysis Centers, the largest part of the program, over the next four or five years should have the capacity to sequence thousands of human genomes from individuals in specific disease cohorts.

Under the new plans, the Sequencing Centers, which according to NHGRI have seen their budgets drop by around 10 percent per year since the completion of the human genome sequence, would see a budget decrease of around 18 percent overall in the first year.

These centers will continue to make up roughly 80 to 85 percent of the overall program, and will maintain their emphasis on priority projects, such as understanding the genomic basis of complex disease, sequencing whole genomes of thousands of individuals from disease cohorts, more studies of the genomic basis of cancer, and others, according to the institute.

Over the next four years, NHGRI plans to create for the program a mechanism that will be used to enable research communities to propose specific sequencing projects, collaborations with other NIH institutes, and projects initiated both by NHGRI and by the Genome Sequencing Centers.

The new mid-sized Center for Mendelian Disorders intends to focus on single-gene disorders. Funded with an expected $10 million, this center will locate appropriate samples, obtain consent for genomic sequencing, and coordinate analysis efforts among research communities. Such a center would be able to resolve the molecular basis of between 40 to 50 Mendelian disorders per year, NHGRI estimates.

The center will provide four years of funding that would make up around nine or 10 percent of the sequencing program. According to NHGRI, there are 1,780 Mendelian disorders and 1,994 more that are suspected to belong to this group, all of which have no known molecular basis.

A center to study these diseases would have to be able to coordinate sample availability, conduct exome sequencing and analysis, and it would need to be a resource for other investigators studying individual Mendelian diseases, said NHGRI.

Another effort will focus on clinical sequencing exploration projects. These programs, according to NHGRI, will require around $5 million per year to stimulate the use of DNA sequence information in the clinic and "begin to bridge the gap between discovery and personalized medicine."

Felsenfeld said that the Clinical Sequencing Center program would be a "mid-sized investment in stimulating the activity of clinicians that understand that they need genomic information about their patients, and to support that activity.

"We have long understood that the ultimate aim is for genomic information to be relevant in the clinic and to individuals," he said.

Most importantly for the clinical program, Felsenfeld added, "the investigators in this case will have contact with the patients and will be intending to use those results for the benefit of the patients."

The remaining $5 million, or four to five percent of the Large-Scale Sequencing Program budget, is expected to be used to fund the Robust Genomic Sequencing Analysis Tools program. This particular initiative aims to "take scientific sequence analysis software from both the large-scale centers and from other sources, and make them robust and broadly available," said NHGRI.

Funding from this part of the program will be used to support R01 grants for robust genomic sequence analysis tools, such as tools for sequence alignment, whole-genome assembly, and variant calling. Because it is not yet clear if the best model for such a program is for public or private grants, this program will include both Small Business Innovation Research and other grants mechanisms.

While large research groups may have access to most of the sequence analysis software they require, Felsenfeld told GWDN that "it's the smaller groups that are now increasingly using the new sequencing platforms to get their own data to run their own projects that are having to look hard for this kind of analysis capacity."

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