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Competition, Politics, and a Pair of Pufferfish

SAN FRANCISCO, Nov. 9 - Rumor has it that well-prepared raw fugu will cause your lips to tingle. The sensation, as sushi chefs will tell you, is the product of a sub-lethal dose of neurotoxin found in the pufferfish. The politics surrounding the recently announced sequencing of fugu and tetraodon, two distinct species of pufferfish, seem to have had a similar non-lethal, but slightly toxic effect.


The Fugu Genome Sequencing Consortium announced the completion of a 5.3-fold coverage draft sequence of the pufferfish Fugu rubripes  during the 13th Genome Sequencing and Analysis Conference, which ended last week in San Diego. The Consortium is led by the US Department of Energy's Joint Genome Institute and the Singapore Biomedical Research Council's Institute of Molecular and Cell Biology.  

In a less-publicized fashion, and in what some would consider a reaction to the fugu announcement, a group comprising the French National Sequencing Center, or Genoscope, and the Whitehead Institute Center for Genome Research announced that they've completed sequencing their own  pufferfish, a six-fold coverage of  Tetraodon nigroviridis.  


From a genomic perspective, the two fish appear very similar: In one corner, Fugu, a saltwater denizen, weighs in at approximately 365 million bases, while the fresh-water Tetraodon boasts 380 million nucleotides.


They are also relatively the same age: about 20 million years apart, compared to the approximately 400-million-year interval between the emergence of puffers and humans.


This apparent competition between the two research consortia is due to the puffers' potential utility as a tool to help researchers better understand human genes. The fish share many genes with humans, but without the huge number of repeats that swell the human genome to its billion-base size. 


The two pufferfish's approximately 380 million bases versus the human's 3 billion also make it much cheaper and faster to sequence.


"This organism has been interesting people for a long time," said Jane Peterson, a program director at the National Human Genome Research Institute. "There was an argument early on to do [pufferfish] before humans."


So that a pufferfish was sequenced came as no surprise to the scientific community. But why necessarily sequence both species?


The answer is perhaps as much political as scientific.


The salty, toxic one ...


In the fugu corner there is British molecular geneticist Sydney Brenner, who has been perfecting and advocating the fugu sequence project since 1989. 


Brenner for many years had a vision and a plan to sequence fugu, which is typically found in the waters off Japan. What was missing was the funding. He said he approached the Scripps Research Institute, the Department of Energy, the National Institutes of Health, and the Wellcome Trust to sequence the saltwater fish, but to no avail.


"In the end, I just basically gave up," Brenner said in an interview. 


But in the summer of 2000, Brenner gave a talk about the fugu at the Joint Genome Institute, based in Walnut Creek, Calif., where the Institute's director, Trevor Hawkins, happened to be listening. The ball began to roll from there.


"I was astounded that nobody had plans to sequence fugu," explained Hawkins. "I spoke to the [JGI] advisory board, and it was approved."


Through the JGI, together with Singapore's Institute of Molecular and Cell Biology-which supplied funding to buy sequencing services from Celera Genomics and Myriad Genetics in what Brenner described as a "cash for sequence, no questions asked" deal-the fugu sequence was born. 


The Fugu Genome Sequencing Consortium's next steps, said Brenner, include filling in sequence gaps, annotation, and analysis of the genome.


... or the fresh, non-lethal one


Tetraodon comes from rivers and estuaries in Indonesia, Malaysia, and India, south of fugu's home turf. In 1997, Frenchman Jean Weissenbach, director of Genoscope, began sequencing its genome. Three years later Weissenbach enlisted the sequencing help of Eric Lander's group at the Whitehead Institute, in Cambridge, Mass. 


"In 1997, it was observed that annotating human genes was much more difficult than expected," explained Hugues Roest Crollius, the Genoscope scientist in charge of tetraodon sequence analysis. "John Weissenbach thought, 'Why not sequence a different vertebrate genome and through comparison see which genes were conserved and bypass some of the sequence annotation problems?' Sequencing a fish seemed like a good choice ... and Tetraodon was a good fish to choose because of its compact genome."


Meanwhile, Brenner said he felt the same way about using a pufferfish, specifically fugu, to help decode human genes. Humans and fish, after all, are "the same systems separated 400 million years ago," he explained. 


But why not pool resources and choose one fish to sequence?


A case for two puffers


"The tetraodon project was started in 1997," said Roest Crollius. "The question is why did the fugu people decide to sequence fugu in 2000?" 


Responded Brenner, who dates his efforts sequencing fugu earlier: "They could have always collaborated with us." 


JGI and Whitehead, which have worked closely together on the Human Genome Project, according to NHGRI's Jane Peterson, are known to be competitors on projects other than the pufferfish.


"This is not the only example of JGI and Whitehead going head to head," said Hawkins. "We announced we were [going to sequence the sea squirt Ciona intestinalis ], and then Eric [Lander] announced he was going to sequence the other sea squirt, Ciona savignyi."  


"It's healthy competition," said Hawkins. "I used to work with him, and now we're going head to head."


Lander did not respond to a reporter's request for comment.


Hawkins also pointed to a phenomenon that is not unheard of in science: two groups reaching similar conclusions and experimental results in the same time frame. "We are both pushing the envelopes in genomics. Sometimes you come up with the same approaches and ideas," Hawkins said. 


In fact, both groups concede that sequencing two species of pufferfish may be better than sequencing just one.


"The two genomes are very close, approximately 20 million years apart," said Roest Crollius. "There might be interesting things to learn from comparison of two pufferfish."


Hawkins agreed: "Two fish are better than one. They are similar fish, it will be interesting to learn their similarities and differences."


"It's great having two fish genomes," said Evan Eichler, an evolutionary biologist at Case Western Reserve University. "It makes evolutionary comparison much more valid. When you have one representative of any phylum or group, the argument is that 'Is it representative?'"


"Having two representatives allows you to say, 'Have these genes been lost or are they just representative of this particular species?'" Eichler explained. "It provides validity, a back-up to what you're observing in one species or another. For evolutionary biologists it makes perfect sense." 


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