For basic biological research and drug discovery, the front-runninganimal model is Mus musculus _ the mouse. But mice do have onedrawback: Lab technicians often develop warm personal feelingstoward these soft, furry sacrificial creatures.

At the other end of the lovability scale skulks Fugu rubripes, thepufferfish. This prickly skinned, highly toxic, seagoing vertebrate caninflate its blimp-shaped body to the sphericity of a balloon,presumably to scare off predators, and frighten its own prey intosubmission.

Yet fugu is itself prey to Japanese gourmands, for whom speciallytrained chefs dissect out the pufferfish's poisonous flesh. And nowthe pufferfish looks like it's becoming quarry for genomic genehunters.

Although the DNA endowments of F. rubripes and Homo sapiensdiverged some 475 million years ago, their respective genecomplements display a striking _ and possibly useful _ similarity,as well as one major difference, namely, size.

Human genomes measure about 3,000 megabases, whereas the fugumakes do with 400 Mb, which is 7.5-fold smaller. What's more (orrather less), only 7.6 percent of the puffer's compact genome goesinto repetitive DNA or ribosomal genes, leaving 92.4 percent asunique gene sequences. By comparison, only 40 percent of the humangenome is unique.

"The distance between genes is smaller in the fugu," Britishmolecular biologist Michael Trower told BioWorld Today. "So theamount of junk DNA," he added, "is much less in pufferfish than inman." Trower is a group leader in the genomics unit of Glaxo-Wellcome Medicine Research Center in Stevenage, U.K.,

"Fugu's introns are smaller," he observed. "Whether they once hadbig introns that became smaller, or small ones that never grew, noone knows. But both life forms contain approximately the samenumber of genes in their genomes."

Three years ago, pioneer molecular biologist Sydney Brenner, atBritain's University of Cambridge, proposed (in Nature dated Nov.18, 1993), "Because F. rubripes has a similar gene repertoire to thehuman genome, it is the best model genome for the discovery ofhuman genes."

Fugu's DNA Keeps Gene Hunter's Promise

Now he and 13 collaborators have made good on that suggestion witha report in the current Proceedings of the National Academy ofSciences (PNAS), dated Feb. 20, 1996. Its title: "Conservation ofsynteny between the genome of the pufferfish (Fugu rubripes) and the[long-arm] region of human chromosome 14 (14q24.3) associatedwith familial Alzheimer's disease (AD3 locus)."

That paper's first author is Glaxo-Wellcome's Trower. "Synteny," heexplained, "means having the same genes in two genomes, and theyare in the same order."

He recalled, "Last year, we were looking at a particular region of theAlzheimer's disease (AD) locus, which was quite big. So we thoughtwe would apply the pufferfish genome to see if it would help us turnup any genes."

Brenner had created fugu genomic libraries at Cambridge. Trower'steam subjected this resource to PCR analysis, computerizedhomology study and sequencing, rather than teasing out DNA fromthe living fish.

Working with the University of Toronto's veteran AD investigator,Peter St. George-Hyslop, the British group selected a number ofknown and candidate AD genes, and tried to find them in the fugugenome.

Co-author St. George-Hyslop told BioWorld Today: "At the time, wewere attempting to find the best technology for finding genes in thequickest way. So the pufferfish was one way we thought of.

"The first step," he continued, "was to see whether or not there wassufficient synteny that it would in fact be as useful as we had hoped.Indeed," he added, "some of those genes turned up in the syntenicregion of the pufferfish, indicating that the method [Brenner hadproposed] was a very reasonable one."

St. George-Hyslop said he thinks of the fugu connection as "one ofthe complement of things that people can now use to hunt for diseasegenes. If you have adequate sequencing techniques, then this is a veryefficient way of selecting candidate genes."

On To Migraine And Other Disorders

In the summer of 1995, by other techniques, St. George-Hyslopreported discovering and cloning an AD gene on human chromosome14, found in early onset Alzheimer's disease (see BioWorld Today,Aug. 18, 1995, p. 1). That gene is now known as presenilin 1.

And this month's Nature Medicine carries a report from HarvardMedical School investigators titled: "Alzheimer-associatedpresenilins 1 and 2: Neuronal expression in brain and localization tointracellular membranes in mammalian cells."

Glaxo's Trower observed: "Now that presenilin 1 has been identified,we've moved on to other projects, using the pufferfish as a tool forpositional cloning." Among those other disease targets, he allowed"is a migraine project for which we have a conserved gene." Headded, "I can't release any other information at this time." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.