Puffer fish joins genome stampede

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Tokyo & Washington

Economy size: Fugu has as many genes as humans and mice, but a much smaller genome. Credit: KATSUTOSHI ITO

An international consortium led by the US-based Joint Genome Institute last week announced plans to sequence the genome of the puffer fish Fugu rubripes. It is hoped that this will offer a cheap and fast route to unravelling many of the mysteries of the human genome.

Since the draft sequence of the human genome was announced in June, annotation of the sequence — allocating genes to pieces of sequence — has progressed relatively slowly. Comparative analysis with other vertebrate genomes is thought to be the key to illuminating many of these genes and regulatory sequences, and another consortium has already announced that it will produce a draft of the mouse genome by next March (see Nature 407, 663–664; 2000).

The Fugu genome, also expected to be ready in draft form by next March or April, should make finding the genes a much faster process than if only the human and mouse genomes were to hand. “It's going to have a pretty dramatic effect,” says Trevor Hawkins, deputy director of the Joint Genome Institute (JGI). “I can't quantify it, but it's going to be pretty amazing.”

The JGI, which is based at the Lawrence Berkeley, Lawrence Livermore and Los Alamos national laboratories, will use a procedure called the whole-genome shotgun technique. This breaks the genome into fragments, after which 84 automated sequencers will analyse the 400 million base pairs of DNA in the Fugu genome. Raw sequence data will be released every 24 hours, in accordance with the public project's policy. Scientists can then use these gene fragments to run searches against genes or potential genes in other organisms.

By March, the JGI should have sequenced the fish's genome at least three times over, covering 95% of the genome. This should provide enough data to assemble the fragments into contiguous stretches of DNA, and allow comparisons with the mouse and human genomes.

“I want to take it higher,” says Hawkins. Higher coverage, perhaps to four or five times, would result in longer stretches of unbroken DNA, and therefore better comparisons.

Other members of the consortium include Singapore's Institute of Molecular and Cell Biology (IMCB), the US Institute of Systems Biology in Seattle, the UK Human Genome Mapping Project Resource Centre, and the US Molecular Sciences Institute in Berkeley, California. They will share the computational load and be responsible for 'finishing' the Fugu genome by putting together the fragments produced by the JGI's shotgun technique. The finishing phase is expected to be complete by the spring of 2002.

The Fugu genome is thought to have about the same number of genes as the human genome — 60,000 to 65,000, according to estimates by IMCB's B. Venkatesh. But the Fugu genes are spread over only 400 million DNA base pairs, compared with some 3 billion base pairs in the human and mouse. “It can be thought of as the minimum set of genes to build a vertebrate,” says Venkatesh.

Comparing Fugu and human “is a very cheap way to get a gene catalogue”, says Jean Weissenbach, director of the Centre National de Séquençage in Evry, France. This spring, Weissenbach used the partial sequence of a related puffer fish, Tetraodon nigroviridis, to predict that the human genome has 28,000–34,000 genes. He expects the Fugu sequence to confirm that estimate.

And because that genome contains few repeats or 'junk' DNA, it should be easier to find similar sequences — and hence genes — between Fugu and human. Human, mouse and Fugu genes all share exons — lengths of DNA that code for proteins. But in the two mammalian genomes, some introns — stretches of DNA that are not translated into the final protein — also come as part of the package. Having Fugu's sequence will help weed out those non-coding areas, says Weissenbach.

For IMCB's Chris Tan the project is both a way for Singapore to develop in bioinformatics and biocomputation and a way to move genomics beyond sequencing to “really exciting applications and functional analysis”.

http://jgi.doe.gov/tempweb/programs/fugu.htm

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