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By Brian Reid

July 11, 2002 | As genome decoders close in on the final draft of the human genetic blueprint, the National Human Genome Research Institute (NHGRI) has laid the groundwork for the encore.

The NHGRI in May targeted the next set of six “high priority” organisms to be sequenced with federal funding. The set includes the chimpanzee, the chicken, and the honeybee.

Though those projects will not carry the attention or prestige of the human or mouse sequencing projects, the technology and techniques used to crack this new set will build on everything learned during the race to finish the human genome.

The sequencing capacity of the centers involved in the work exploded during the 1990s as pressure built to generate the human data, and it should allow the new set of genomes to be decoded at pace that will dwarf that of even the human project.

The biggest obstacle to the quick completion of the new targeted genomes will be money, not technology, according to George Weinstock, co-director of the Human Genome Sequencing Center at Baylor College of Medicine in Houston.

“The capacity exists in the large centers,” Weinstock says. “It will be limited by the dollars, not the sequencing capacity.”

The NHGRI, a division of the National Institutes of Health (NIH), currently spends $155 million a year to support work at sequencing centers, with the bulk of that money going to three large-scale sequencing centers: the Baylor College of Medicine’s center; the Whitehead Institute’s Center for Genome Research at MIT in Cambridge, Mass.; and the Genome Sequencing Center at the Washington University School of Medicine in St. Louis. The funding is divided among the human, mouse and rat projects.

The new projects vary in their estimated cost and time commitment. The chimpanzee project, for example, is expected to run about $100 million, but the honeybee is pegged at just around $7 million. That compares to the $300 million the NHGRI estimates was spent on the creation of the rough draft of the human genome. Work on the six new organisms could start later this year.

The NHGRI used a unique system to decide which organisms would get the genome spotlight next as work on the human, mouse, and rat genome programs wound down. Because the money to keep the sequencing centers running had already been allocated, the NHGRI assembled a panel of researchers to advise it on choosing the next set of organisms.

The group examined an assortment of white papers with brief arguments about why a specific organism should have its genome decoded. After analyzing the information, the group designated six high priorities: chicken, chimpanzee, honeybee, sea urchin, a group of fungi, and a protozoan Tetrahymena. The panel’s recommendations were then reviewed and approved in May by the National Advisory Council for Human Genome Research, an advisory committee established by the NIH.

The plans for the sequencing of each organism differ, but nearly all of the projects suggest a marriage of the two competing genome-sequencing strategies: the laborious but accurate bacterial artificial chromosome (BAC) method, and the quick whole genome shotgun (WGS) approach championed by Celera Genomics during its effort to decode the human genome.

“There is no golden path for the best way to do sequencing, still,” says Larry Thompson, a spokesman for NHGRI. “The work we did on the mouse was whole-genome shotgun. With the new programs, they were able to assemble it and get a much larger assembly than anyone expected. You can get pretty far now doing whole-genome shotgun.”

That strategy will provide the basis for the future efforts, though the groups planning to sequence the organisms have tailored their strategies to the needs of the researchers. A perfect clone-by-clone approach may prove vital for some groups, but most of the proposed genome projects will rely on a mixture of strategies.

“In general, as with most information problems, the right strategy depends on how you’re going to use the information,” says Eric Lander, who directs the sequencing effort at the Whitehead Institute.

Figuring out what researchers need, Lander says, drives the techniques used in each individual case. For example, one project’s goal might be to knock off less-than-perfect sequences that rely on WGS used in tandem with the BAC approach, ultimately yielding a wealth of scientific information that can immediately be compared to existing genome information.

A similar strategy was used in the mouse genome project, and it could also be used in the chimpanzee analysis, one of the projects Lander said he expects to begin later this year. Rather than targeting a painstaking genome map as the final goal, researchers would merely look for areas in which the human and chimpanzee differed.

The sequencing of other organisms will likely rely on a similar mix. The white paper for the honeybee notes that BAC and WGS should be used, but that a full, finished sequence is not needed. And Weinstock says the sea urchin project likely will also use a mixed strategy. The smaller, less complex genomes are likely to be done solely through the WGS method.

The technology -- from the sequencing machines to the hardware and software responsible for placing the genetic sequences in order --- will not be radically different from the equipment that has powered past projects, but steady advances should continue to speed the process.

 “We’re taking advantage of better computer hardware,” says Richard Wilson, the co-director of the Washington University sequencing center. Lander and Weinstock, too, lauded evolutionary changes in the assembly software.

“When we started the human genome at the start of 1999, there was a question of whether the centers would be able to do it in the timeframe we had set,” Weinstock says. “Now, all of those centers have developed their sequencing technology, their assembling software, and all the other things, so that any one of them could knock it off in the same amount of time.”

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