By Julia Karow
This article was originally published May 27.
The National Human Genome Research Institute will continue to fund several big genome centers as part of a renewal of its large-scale sequencing program, and plans to add a mid-sized Center for Mendelian Disorders, exploratory clinical sequencing, and sequence analysis software development to the program.
At a meeting last month, NHGRI's National Advisory Council of Human Genome Research approved recommendations by managers of the program, which is up for renewal in fiscal year 2011. NHGRI plans to issue a request for applications this fall, and make awards in the fall of 2011.
The program is currently funded with approximately $110 million per year over four years, and the proposed renewal "could benefit from a similar amount," according to NHGRI. That number could still be revised in either direction, depending on budget constraints and how the program will be balanced against other priorities at NHGRI, according to Adam Felsenfeld, a director for the large-scale sequencing program.
Over the last several years, the program has supported three genome centers that make up NHGRI's Large-Scale Sequencing Research Network: the Broad Sequencing Platform at the Broad Institute; the Human Genome Sequencing Center at Baylor College of Medicine; and the Genome Center at Washington University School of Medicine.
These centers have been involved in a variety of sequencing projects, the most prominent being the Cancer Genome Atlas — a joint project between NHGRI and the National Cancer Institute — and the 1,000 Genomes Project, which also involves international partners.
For the renewal, NHGRI managers proposed to continue funding several large-scale sequencing and analysis centers at a reduced overall level, and to add three new initiatives: a mid-sized Center for Mendelian Disorders; exploratory clinical sequencing projects; and the development of robust genomic sequencing analysis tools.
Large Genome Centers
Under the current proposal, 80 to 85 percent of the new funding, or about $90 million per year over four years, would go to large-scale genome sequence and analysis centers. That would mean an 18-percent overall funding cut for these centers from the current level in the first year, though NHGRI noted that it has already cut the centers' budget by about 10 percent per year since the completion of the human genome project.
The centers will address "major opportunities," such as understanding the genomic basis of complex disease, for example by sequencing whole genomes "of thousands of phenotyped individuals from disease cohorts or prospective studies," or by studying the genomic basis for cancer, according to the institute.
Projects of this type, NHGRI said, still "require a degree of scale and organization that are appropriate for large-scale centers." These will continue to offer state-of-the-art high-throughput sequencing, be "flexible enough" regarding the sequencing technologies and analytics they offer for different types of projects, and implement new technologies, among other features.
According to Felsenfeld, NHGRI plans to fund at least two large-scale centers, and applicants need to have "an adequate infrastructure" in place with regard to sequencing instruments, informatics, and overall expertise.
NHGRI will continue to use several mechanisms to select sequencing projects to be tackled by these centers, including community-proposed projects, collaborations with other NIH institutes, NHGRI-initiated projects, and projects initiated by the centers themselves.
Center for Mendelian Disorders
Nine to 10 percent of the proposed funding, or about $10 million per year over four years, is earmarked for a Center for Mendelian Disorders that will use exome sequencing to find mutations underlying most or all single-gene disorders, "an opportunity that fits well with the concept of a dedicated, mid-sized center," NHGRI said.
The new center would coordinate the availability of samples, maintain a state-of-the-art exome sequencing and analysis capability, be a resource to investigators seeking genes underlying a particular Mendelian disease, and involve interested disease research communities in the analysis. At full scale, it would be expected to solve on the order of 40 to 50 disorders per year, and collect samples for all remaining unsolved Mendelian disorders over the term of the grant.
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According to the institute, there are currently 1,780 Mendelian disorders and another 2,000 or so diseases suspected to be Mendelian in nature that have no known molecular basis.
"Exome sequencing is working quite well technically," Felsenfeld said, and there is now strong proof-of-principle from several studies that it can be used to find the molecular basis for a Mendelian disease by sequencing just a handful of individuals. "This is something that people have been talking about for years, and now it's finally possible to answer that question as a concerted effort, and we think it's time to try that," he said.
Last year, NHGRI funded a group at the University of Washington to study Mendelian diseases using exon sequencing (IS 2/9/2010), an award made with stimulus funding under the Medical Sequencing Discovery program. That project is modest in scale and will be studying about 20 diseases per year, Felsenfeld said.
The proposed center will be larger and bring together samples and disease expertise from many different places. "The idea of trying to be comprehensive about Mendelian disorders is something that requires quite a lot of organization," he said, possibly "as much organization as sequencing prowess."
NHGRI specified exome sequencing rather than whole-genome sequencing for the new center for economic reasons. "Right now, whole-genome sequencing is a lot more expensive," Felsenfeld said, estimating that it is probably ten-fold higher.
He acknowledged that exome sequencing may miss the molecular basis of some Mendelian diseases, but "it's perfectly reasonable to think that you might get a large percentage of these with exome sequencing …and then you may have to go back and try other things with the ones you did not get."
Exploring Clinical Sequencing
About 4 to 5 percent of the program's funding, or an estimated $5 million per year over three years, would go to clinical sequencing exploration projects. This initiative aims "to stimulate the use of sequence information in the clinic to begin to bridge the gap between discovery and personalized medicine," according to NHGRI.
The institute plans to fund approximately five projects where a clinician wants to "obtain substantial sequencing and other genomic information" from patients — generated by a local facility or other service provider — in order to inform their diagnosis, prognosis, or treatment.
NHGRI believes this component will be an opportunity to gain insight into the best clinical uses of genomic sequencing, project design, and analysis requirements, and to address ethical, legal, and social issues such as patient consent, data release, patient communication, and regulatory issues.
Another 4 to 5 percent of the program, or about $5 million over four years, is set aside for the development of genomic sequence analysis tools.
According to NHGRI, there is a need for robust, well-documented and well-supported informatics tools for sequence analysis. While such tools exist and work well at the large-scale sequencing centers, they have not been adapted to the needs of other groups getting involved in genome sequencing. Thus, the plan is to fund projects that will take sequence analysis software from the large-scale centers as well as "other sources" and make them robust and broadly available.
Felsenfeld said that the institute will seek proposals from both academic groups and for-profit companies. One the one hand, he said, academic research groups are used to building good research-grade software but generally do not tend to provide extensive documentation and user support. With company-supported software, on the other hand, "people worry about whether there can be a sustainable business model built around selling and supporting such software because of the number of users," he said, though the number of users for sequence analysis software has been increasing rapidly.
Several aspects of the current plan for the program's renewal might still change, including the total amount of funding and how it will be apportioned between the four components. Also, the program directors are aware of the rapid pace of change in sequencing technology and the best models for applying it.
"That's actually one of the challenges of this kind of planning," Felsenfeld noted. "You plan, you incorporate things, you write something down in a document, and by the time you can make a funding decision, everything has changed. We just have to live with that and we hope we are flexible enough to be able to take best advantage of how things change."