Second choice: the complete mouse genome sequence may be forced to take a back seat. Credit: TEK IMAGE/SPL

Mouse geneticists are expressing concern that completion of the mouse genome sequence could be delayed because of increasing pressure to sequence the genomes of other animals. The doubts were voiced at a recent workshop organized by the National Institutes of Health (NIH) to set priorities for resources for mouse genetics and genomics.

The mouse was selected two years ago as the second mammalian species, after humans, to have its genome sequenced both by a public consortium led by the NIH and by the private company Celera. This is because the mouse is widely considered to be the best-understood species genetically.

The number of mutant mouse strains is growing rapidly. These are being generated using technologies that ‘knock out’ targeted genes and by random chemical-mutagenesis screens, where mice are exposed to a mutagen and those displaying interesting new traits are selected for breeding. Many of these mutant strains are potentially important models for human disease, and accurate information about their gene sequences will help to unravel the molecular bases of these diseases.

Within the past year, the NIH has set up 10 centres to sequence the mouse genome, and plans to divert capacity in human genome sequencing centres over to the mouse as the human genome nears completion. But many other species, from the zebrafish to the rat, are also vying for the attention of sequencers.

“We always understood that the mouse genome would be finished, but learnt only at the workshop that a firm decision had been taken only for a working draft,” says Rudi Balling, director of the Institute for Mammalian Genetics at the National Research Centre for Environment and Health in Munich.

So far, the mouse sequence is more advanced in the private than in the public domain. Last week Celera announced that after only two months it has sequenced more than a billion base pairs of the 129/SvJ mouse strain, the strain most often used to generate knockouts. This is estimated to be around one-third of the full genome.

Celera's president, Craig Venter, says the company will have the finished, assembled sequence by next summer. Correct assembly of the vast number of base pairs will be relatively easy, he says, as it can be directed by the blueprint of the human genome. This ‘humanized mouse genome’, as Venter calls it, will help to pinpoint genes on the human genome and help to identify gene-regulatory areas, he says.

But Celera's mouse genome sequence will be restricted to the company's subscribers. The public consortium, with its slower but more exact approach, is aiming for a ‘working draft’ of the genome of the C57BL/6 mouse strain — widely used in genetic and immunological studies — well before its original target date of 2003, says Elke Jordan, deputy director of the NIH's National Human Genome Research Institute.

She declines to put a date on finishing, saying that in principle the NIH's commitment to finish “remains unchanged: it's what everybody wants”. But she says there are “too many uncertainties about funding” for a date to be fixed.

This view is echoed by Eric Lander, director of the Whitehead Institute at the Massachusetts Institute of Technology. “There is tremendous enthusiasm from all quarters to finish the mouse genome, and scientists won't have to wait very long,” he says.

But he admits that “the importance of a lot of different projects will have to be juggled, and it'll all get done in an order that is maximally useful to scientists as a whole”. Like the NIH, Germany and France are waiting to assess the scientific promise of different species before committing their national sequencing efforts to finishing the mouse.

Jordan points out that the public consortium, concurrent with providing a working draft, will finish selected areas of the mouse genome judged to be biologically important. Although primarily intended to support priority areas of mouse genetics, this “will also give us a better idea of how much better it really [would be] to have the finished sequence”, she says.

Mouse geneticists need no such convincing. “A draft sequence will be a poor tool for mouse geneticists,” says Phil Avner, head of the mouse molecular genetics unit at the Pasteur Institute in Paris. It will allow no more than 80 per cent of genes to be identified, and will not provide key information about areas of the genome that regulate the genes, he says.

Even some zebrafish geneticists agree that finishing the mouse genome is a high priority because of the uniquely advanced level of genetic tools available. “But zebrafish biologists will also need a working draft within the next year or two,” says Wolfgang Driever, a zebrafish geneticist at the University of Freiburg. “So ultimately it will be a question of timing and funding.”