Genome of Ancient Fish Could Reveal Evolutionary Mysteries, Stanford Scientists Say.

STANFORD, Calif. -- A prehistoric fish that until 1938 was thought to be extinct has caught the eye of geneticists at the Stanford University School of Medicine who hope to sequence the ancient genome to learn how animals evolved to live on land.

The 5-foot, 130-pound fish in question, called the coelacanth, ekes out an existence in cool, deep-water caves off the Comoro Islands in the Indian Ocean and northern Indonesia. Its lobed fins, skeleton structure and large, round scales are practically unchanged from its fossilized ancestors. This resemblance is what makes it an attractive target for sequencing, according to work published in this week's online issue of Genome Research.

Genetics professor Richard Myers, PhD, co-authored the paper, which makes the case for sequencing the coelacanth genome. "It's just making an argument that if we want to understand this level of evolution, this is what we need to do," he said. The next step is convincing a funding agency, such as the National Institutes of Health or the Department of Energy, to add the coelacanth to a list of high priority organisms to sequence.

Geneticists often compare gene sequences between species to learn how traits evolved. To learn what makes a mammal a mammal, for instance, they may compare a gene sequence in humans, mice, dogs, chickens and frogs to see what sequences the mammals share and that frogs and chickens lack. If all the mammals have one sequence in common, it is likely to be important for making milk, growing hair or other features unique to mammals.

This type of analysis has been all but impossible for learning how land animals crawled ashore and developed limbs and lungs. The problem is this: as fish evolved they went through a flurry of genetic alterations, making fish species almost as different from each other as they are from land animals. Given this vast diversity, a sequence in land animals that's missing in one of the fish species is not necessarily involved in land animal biology, according to James Noonan, PhD, who did the coelacanth work as a graduate student at Stanford with Myers, the Stanford W. Ascherman, MD, FACS Professor in Genetics. That genetic difference may just be the result of random changes in that particular fish.

In contrast, the coelacanth seems to have changed very little -- physically or genetically -- since one wayward branch of the fish family headed for land roughly 360 million years ago. Because it has changed so little the coelacanth is ideal for genetic comparisons. Any genetic feature found in all land animals but lacking in the coelacanth could represent a change that makes living on land possible.

Noonan said that coelacanth's close relative, the lungfish, could also fill in the genetic gap between land animals and fish, but the coelacanth has one practical advantage: "The lungfish genome is enormous," said Noonan, who is now a postdoctoral fellow at the Lawrence Berkeley National Laboratory. At 35 times the size of the human genome, sequencing the lungfish is an unlikely proposition. In contrast, the coelacanth genome is smaller than that of either humans or mice.

To make his case for the coelacanth, Noonan sequenced a group of coelacanth genes called the protocadherin gene cluster. He chose this region because it is extremely variable between different species, making it easy to see differences and similarities. This region has 54 genes in humans and 97 genes in the zebrafish, whose genome has been sequenced. He found that the coelacanth had 49 genes in the cluster, much like humans and other land animals. What's more, humans and coelacanths both have subgroups of these genes that zebrafish lack. "The coelacanth is evolving very slowly, that's what makes them interesting," Noonan said.

Although it isn't known why coelacanths evolve so slowly, Noonan suggested that their lifespan might be at issue. Where most fish reproduce quickly and have short generation times, the coelacanth reproduces slowly and gives birth to live young. This means that the coelacanth has had fewer generations of offspring to accumulate mutations.

The fact that coelacanth is available for sequencing is a lucky accident. They were thought to be extinct until 1938 when museum curator Marjorie Courtaney-Latimer discovered a specimen in a fisherman's catch near Cape Town, South Africa. In 1998 a honeymooning researcher found a second population off the coast of Indonesia.

Last year Myers and David Kingsley, PhD, professor of developmental biology, successfully recommended that a fish called the stickleback be added to the list of organisms to be sequenced by the National Human Genome Research Institute at the NIH. Myers said he, Noonan and other researchers who contributed to the article in Genome Research will be submitting the coelacanth for consideration soon.

Other Stanford researchers at the Stanford Human Genome Center who contributed to this work include Jane Grimswood, finishing group leader; Jeremy Schmutz, informatics group leader, and Mark Dickson, production sequence group leader.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions -- Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.