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Zebrafish to be Sequenced: Could be Next Knockout Mouse

NEW YORK, Feb 12 - The next knockout mouse may have fins.

Monday, the Sanger Center was scheduled to begin a three-year project to sequence the tiny zebrafish, Danio rerio , which is thought to be an optimal model organism for discovering gene function, according to Tim Hubbard, the center’s director of genomic analysis.

Although the zebrafish genome is half the size of the human genome, researchers have developed precise tools to generate and analyze alterations in it, enabling them to perform comparative genomics experiments similar to those performed in transgenic, or “knockout,” mice.

The zebrafish is suited to model organism genomic studies because the female lays up to 200 eggs per week and because the results of genetic alterations can be clearly seen in the zebrafish embryo, which is transparent and develops outside the female’s body, clearly displaying stages during the two- to three-month period of its development.

The Sanger Center may complete its zebrafish project sooner than its three-year target because it is using ABI's new POP-37 performance optimized polymers with its ABI 3700s, Hubbard said. These polymers, which are updated from earlier products called “POP-5” or “POP-6,” separate DNA fragments of a known size range for a desired resolution and run time.

POP-37 “allows you to do more runs per week,” he said. “When we started using it, our reads per month broke three million.”

Christiane N sslein-Volhard, a 1995 Nobel prize winner from the Max-Planck Institute, pioneered the use of the zebrafish in the early 1990s as a model organism for studying the genetics of vertebrate development. She and other scientists have located over 1200 zebrafish mutants.

Stefan Schulte-Merker, one of N sslein-Volhard’s original graduate students in these zebrafish experiments, has lately been using the zebrafish in his work at Artemis pharmaceuticals to search for genes that could be useful in developing drug targets

Schulte-Merker and his colleagues have isolated a gene for increased bone formation in the zebrafish, he said at a presentation last week to the Advances in Genome Biology and Technology conference in Marco Island, Fl. “If you care about osteoporosis and similar diseases, this is certainly a gene worth looking at.”         

They have also looked at genetic mutations that may be key to preventing tumor angiogenesis.

The Artemis researchers use an antisense inhibitor, morpholine, that will knock out genes in the zebrafish embryos. The only problem with this technology, said Schulte-Merker, is that it cannot work well with late-acting genes.  

But other than this limitation, he said, “genome research [on the zebrafish] is ever expanding.”

The Sanger Center’s zebrafish genome data will be available almost immediately to researchers without charge.

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