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NHGRI White Paper Questions Scientific Community About Future of Genome Sequencing

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As part of a strategic planning process for its future activities, the National Human Genome Research Institute last week posted a white paper with questions about the future of genome sequencing on its website and is currently seeking feedback from members of the scientific community.

Sequencing will likely become more decentralized in the future, and new sequencing technologies with lower costs will continue to drive new research applications, according to NHGRI officials.

Community members have until Feb. 27 to comment on the white paper’s questions, and submit additional ones. After that, through mid-May, scientists will be asked to answer the questions.

New DNA-sequencing platforms, according to the white paper, have become a “disruptive technology” that will create new research opportunities in the next decade.

“The availability of these so-called ‘next-gen’ sequencing technologies (and the already emerging ‘third-generation’ technologies that will closely follow) raises many questions for the research community,” the paper states.

One set of questions focuses on how sequencing projects should be organized in the future, in particular, whether sequencing and data analysis should continue to be carried out by large, centralized genome centers, or whether it should become more decentralized.

For example, the questionnaire asks whether there are “important projects that only such large centers can accomplish,” and about the merits of “encouraging the ‘de-centralization’ of sequencing.”

Right now, under its “large-scale genome resequencing program,” NHGRI funds three genome centers: the Baylor College of Medicine Human Genome Sequencing Center, the Broad Institute Genome Sequencing Center, and the Washington University Genome Center. These centers provide large-scale sequencing capacity for a variety of research programs. In addition, NHGRI funds its own intramural sequencing center, NISC.

In fiscal year 2008, which ended Sept. 30. 2008, the program doled out approximately $31.6 million for Baylor, $48.8 million for the Broad Institute, and $35.7 million for WashU, according to NIH databases.

However, this centralized funding approach might change in the future as more institutions establish considerable sequencing capacity outside of the large-scale sequencing program.

According to Adam Felsenfeld, program director of large-scale sequencing at NHGRI, “I think it’s been the last year that brought all of it home, because of the real increase that can be produced not just by the centers that we fund but by groups outside of what we fund, and also by what we previously would have considered smaller groups, groups operating at lower capacity, that are now going to be able to operate at quite high capacity.”

Asked whether sequencing through NHGRI might become less centralized in the future, he said that “what we are trying to get out of the questions is, ‘What is the potential for that?’ and ‘How should it be done?’”

Another set of questions centers around how the overall increase in DNA sequencing capacity and the falling cost of sequencing impacts research, for example, what kinds of projects investigators will pursue in the future.

“Just being able to think about having that kind of capacity enables you to think about entirely new kinds of projects,” Felsenfeld said.

“The experience has been that as new technologies are introduced, new uses are developed, which had not been anticipated,” said Mark Guyer, director of the division of intramural research at NHGRI. For example, he said, new sequencing platforms have already been applied to transcriptome and structural variation analysis, previously the domain of microarrays and other techniques.

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Other questions ask about the informatics and analysis needs that will arise from the vast amounts of sequence data, and how they should be addressed. One question specifically asks whether researchers will continue to need access to primary sequence data — as they have today through the Trace Archive and the Short-Read Archive — or whether processed data will be sufficient in the future.

A number of questions address the value of continued development of new sequencing technologies and lowering the cost of sequencing further. Since 2004, NHGRI has funded such technology development under its Advanced Sequencing Technology program, dubbed the “$100,000 genome” and “$1,000 genome” grants. Last year, the institute awarded over $20 million in total to 11 research teams through the program (see In Sequence 9/2/2008).

According to Felsenfeld, there is still room for tech development. The $1,000 genome is still a long way off today, he said, and new applications might become possible if the cost drops even lower.

“It may be that right now, we think the $1,000 genome will be a reasonable starting point, but by the time we get close, it may be that there will be compelling reasons to go for the $10 genome,” he said.

Also, it is not only the cost but also the quality of sequencing that will likely improve over time with new tech development. “We can do really good resequencing of especially human genomes right now with paired short read technologies, that’s around, but you could do a lot more if you had very long, cheap reads,” Felsenfeld said.

In addition, high sequencing data accuracy will be indispensable for personalized medicine applications, according to Guyer.

A couple of questions, finally, target how the new sequencing technologies and the data they produce will contribute to improving human health.

Medical sequencing has already increased in the last few years among NHGRI-supported projects, and will likely continue to do so, according to Felsenfeld. “That’s been a steady trend with our program so far, and especially if you look by the amount of capacity that’s devoted to projects, rather than by individual project,” he said.

“Those are some of the most obviously compelling kinds of projects, and there are some very interesting, important sample sets out there on important diseases,” he said.

Overall, the questions in the white paper resulted mostly from internal discussions, according to Guyer, with some input from outside advisors. “I think we have a reasonably good set of basic ideas of what the questions should be, but now we are really testing ourselves by putting them up and seeing what kind of input we will get on the quality of the questions,” he said.

The white paper is one of four such documents on different topics, with more to come. Three other papers pose questions about diagnostics, preventive medicine and pharmacogenomics; therapeutics; and education and community engagement.

The documents are one of several means by which NHGRI aims to obtain community input for its future planning. The agency is also thinking about setting up a wiki for public comment, and holding workshops, webinars, and a large summary meeting.

The tentative aim for having an overall plan for the institute in place is the fall of next year, according to Guyer. The timing of the process will depend partly on when a new NHGRI director will come on board, he said, which is currently unknown.

The last time NHGRI engaged in a strategic planning process was seven years ago, according to its website, leading to a paper in Nature in April 2003 on its “Vision for the Future of Human Genome Research.”

Since then, “the phenomenal advances in genomics and related fields … indicate that it is time for us to look anew at the future of human genome research,” according to the NHGRI website.

The agency already held a meeting with senior scientific staff and “a few outside experts” in April of last year, during which they identified various topics of interest, including large-scale DNA sequencing and its applications, such as medical sequencing, comparative sequencing, and metagenomic sequencing; and sequence-based functional genomics, including disease-specific transcriptome profiles of disease, siRNAs, and microRNAs; the language of gene regulation; and cell states.

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