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Sequencers Examine Priorities

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Science  29 Aug 2003:
Vol. 301, Issue 5637, pp. 1176-1177
DOI: 10.1126/science.301.5637.1176

Now that genomes can be decoded quickly, researchers are debating how to choose which organisms to sequence next

The most conspicuous feature of a recent gene-sequencing meeting in Virginia might have been what was absent: There was no verbal venom between once-cutthroat competitors. Instead, the Whitehead Institute's Eric Lander and former Celera president J. Craig Venter, their race to sequence the human genome behind them, calmly chatted away. Walking by the pair, Edward Rubin, director of the Department of Energy's (DOE's) Joint Genome Institute in Walnut Creek, California, did a double take. “Instead of shooting at each other, they're pointing their cannons in the same direction,” says Rubin.

The invitation-only, closed-door gathering on 21 and 22 July marked a turning point in the world of gene sequencing. There, officials from the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, estimated that in the best-case scenario, over the next 4 years U.S. sequencing centers would generate a staggering 460 billion bases, the equivalent of 22 mammalian genomes. But with all the “obvious” organisms—including the human, the mouse, and the rat—now sequenced, or nearly so, the genetics community and NHGRI, its principal funder, are weighing how to proceed. The country's three massive sequencing centers, fearful of becoming mere factories churning out base after base, are lobbying to preserve influence in choosing which organisms to sequence and analyzing the genetic data they produce. Scientists who mobilized around beloved animals, from the honeybee to the chicken, and won them a spot in the sequencing queue are now wondering what they will target next.

The 30 to 40 prominent researchers who attended the meeting, many of whom commented with surprise on its collegiality, agreed that sequencing should now be driven by biological unknowns rather than popularity contests. “We should turn to using sequencing capacity to answer scientific questions that are of seminal importance,” wrote Princeton University President Shirley Tilghman in an e-mail message. And if that means sequencing an organism “that by biologists' standard is obscure,” she added, “so be it.”

Many participants believe that today's system for prioritizing organisms doesn't capture the most pressing scientific questions. They suggested adding a new layer of four committees to the review process to divvy up sequencing proposals according to scientific goals, such as clarifying evolution or helping shed light on the human genome. Each committee, in turn, would make funding recommendations to an existing NHGRI grant review panel.

The tentative list of new committees includes one to advance annotation of the human genome, another to advance annotation of model organisms, a third to further evolutionary biology, and a fourth that embraces novel organisms—a final opportunity for scientists to promote their pet subjects. The plan is still rough, and the committees “are tremendous overlapping circles,” says Venter, now president and chair of the nonprofit Center for the Advancement of Genomics in Rockville, Maryland.

Many agreed that sequencing priorities are changing and that a new approach is needed for directing the community's now massive sequencing capacity. “If I want to justify sequencing a large number of Drosophila species, I wouldn't be saying, ‘Drosophila's a great organism; there's a large community working on them,’” says Gerald Rubin, vice president of the Howard Hughes Medical Institute (HHMI) in Chevy Chase, Maryland. “I might be arguing, ‘Here's a major unsolved problem in population biology. … [With Drosophila], we can solve this problem.’” Most organisms with a fan club of more than 100 scientists have already been decoded or are well on their way, he adds. The interest now falls increasingly on comparative genomics: overlaying the genomes of multiple species to identify what's been conserved over time, what's been added, and what's been abandoned.

Who's next?

New criteria may determine which organisms join these ones in the sequencing queue.

CREDITS: (TOP TO BOTTOM) ARI KORNFELD; JIM KALISCH/UNL ENTOMOLOGY; TANYA DEWEY/UNIVERSITY OF MICHIGAN MUSEUM OF ZOOLOGY

NHGRI is tight-lipped about whether it will adopt the suggestions of the scientists it brought together. That would be “premature” to discuss, says Jane Peterson, NHGRI's program director for comparative genetics. She expects the institute's advisory council to take up the matter at its meeting in September. Above all, says Peterson, NHGRI wants to ensure that its sequencing priorities are in line with the 5-year plan it unveiled late last year (Science, 29 November 2002, p. 1694). Among the plan's most ambitious goals: to define the function of every part of the human genome.

The role played by the sequencing centers in that process remains in contention. “I hope people are thinking of us as more than just factories,” says Richard Wilson, director of the sequencing center at Washington University in St. Louis, Missouri. (The other NHGRI-funded centers for large-scale sequencing are located at the Whitehead Institute/MIT Center for Genome Research in Cambridge and at Baylor College of Medicine in Houston.)

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DOE's Edward Rubin, whose center focuses on decoding microbes, agrees that the ground is beginning to shift. “There really is tension,” he says. “These people have invested a lot of their lives in setting these centers up, and then to just generate strings of A's and T's that other people consume is a difficult pill.” The tough question confronting gene sequencing efforts, he says, is, “Whose projects are they?”

Some answers may emerge this fall. That's when NHGRI plans to announce new 3-year funding awards to large-scale sequencing centers. The institute is accepting applications beyond those from the big three, and at least a few hopefuls have applied. Among them are Venter's institute and Agencourt Bioscience Corp. in Beverly, Massachusetts.

NHGRI isn't certain how the funding awards will stack up against preceding ones. In the 2002 fiscal year, the institute spent $190 million on large-scale sequencing projects; although the proportion of funds devoted to such work may shrink, NHGRI expects its grantees to churn out more DNA sequence than ever, thanks to declining costs.

With input from sequencers, NHGRI is also trying to determine which method for sequencing organisms is best. “Could we make some shortcuts?” asks Eric Green, the institute's scientific director. His lab is currently assessing the virtues of draft sequences, which are far cheaper to assemble than polished genomes. Venter wryly notes that the whole-genome shotgun method favored by Celera and criticized by NHGRI in the past is now apparently being embraced (Science, 16 February 2001, p. 1182).

The Drosophila community in particular is congregating behind a draft approach, hoping to sequence perhaps dozens of fruit fly species. “I'm completely confident that 10 years from now we'll have the sequences of 50 Drosophila,” says HHMI's Gerald Rubin. Those data could help identify hotspots in the sequence that evolved rapidly and simplify assembly of closely related genomes. NHGRI is currently considering a proposal from Drosophila geneticists to sequence eight species, at a cost of roughly $40 million. That's in addition to two that are already sequenced and two that are approved and in the pipeline.

Implicit in the choice of which genomes to sequence lies a greater uncertainty: If genomes should be selected based on the biological mysteries they could help solve, which mysteries top the list? That was something last month's collegial meeting steered clear of. “It delayed the hard issues,” such as whether to award one vertebrate at the expense of 40 Drosophila, with their much smaller genomes, says Green. Which ones win out, at least in the short term, will be a topic for another day.

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