Zebrafish, humans have new biomedical friend in the spotted gar

That is the conclusion of a comprehensive and international research effort, led by the University of Oregon in collaboration with the Broad Institute at MIT and Harvard University. Researchers sequenced the genome of the gar (Lepisosteus oculatus) - an ancient fish with hard diamond-shaped scales and a long mouth filled with needle-like teeth. Their work is detailed in a paper published online in the journal Nature Genetics.

As the data were analyzed, researchers realized the spotted gar's genome is an evolutionary repository of ancient genetic materials, said UO biologist John H. Postlethwait. "Many genes found in human but not in zebrafish, a favorite for biomedical research, are present in gar, and, likewise, genes present in zebrafish but not in humans are also in gar," he said. "This relic of a fish retains ancestral characteristics lost by other fishes or humans.

In addition, numerous evolutionary conserved, non-coding genetic elements are found in gar that are often tied to human diseases, but they are undetectable in zebrafish directly and so couldn't be studied in the popular medical model, he said.

"The bottom line is that the sequences of non-coding elements have been conserved in humans, gar and zebrafish -- even though they don't code for a protein, they have to be doing something important," said Postlethwait, who also is a member the UO's Institute of Neuroscience. "Now, if you first compare human to gar, and then gar to zebrafish, then we can make the connections. The gar is a bridge."

The discovery, he said, means that biomedical researchers should be able to identify a disease-associated genetic region in humans, locate the corresponding region in the spotted gar and insert it into the appropriate location in the zebrafish or other fish models to potentially understand disease development.

"There are potentially thousands of connections that can be made now," said lead author Ingo Braasch, a postdoctoral researcher at the UO during the project and now a professor at Michigan State University. "This points to a better way to perform biomedical research for studying human disease. With higher precision, researchers will be able to find the right region in the genome of zebrafish to design experiments and mutation models."

The genetic importance is traced to some 450 million years ago, when bony vertebrates split into two major groups. Lobe-finned fishes went one way and ray-finned fishes another. Humans and other limbed creatures emerged along the lobe-finned line. The ray-finned line resulted in so-called teleost fishes that are the most common fish recognizable today: zebrafish, stickleback, salmon, tuna, halibut and about every fish found in a home aquarium.

Gars split off the ray-finned evolutionary line before a genome duplication gave rise to the teleost fishes. The researchers concluded that the spotted gar, by missing that duplication, maintained a conserved genetic makeup, including many entire chromosomes similar to those in the ancestor of bony vertebrates.

"Gar is evolving slowly, which means that it has kept more ancestral elements in its genome than other lineages like for example zebrafish," Braasch said. "Comparisons of human to gar are less confusing because gar does not have all these extra gene copies that zebrafish has from the genome duplication in teleosts."

"By illuminating the legacy of genome duplication, the gar genome bridges teleost biology to human health, disease, development, physiology and evolution," the researchers, including eight associated with the UO, wrote in the paper.

The researchers report that gars are well-suited as genomic and laboratory models. Other non-teleost ray-finned fish groups - bichirs, sturgeons, paddlefish, and bowfin - are problematic due to genetic alterations that have occurred during the evolution of their individual lineages or problems with growing them in the lab. In comparison, it is relatively easy to rear gars in a lab and get embryos for developmental studies.

Gars today are found in U.S. states along the Gulf of Mexico, up the Mississippi River to Michigan in North America, as well as in Central America and Cuba. Spotted gars collected for the research were captured in Louisiana in collaboration with Allyse Ferrara of Nicholls State University.

The spotted gar genome, Braasch said, offers a window into the evolution of vertebrate body plans, including for example how fins evolved into limbs that allowed fish to walk onto land. In addition, gars have enamel-bearing teeth and strong scales containing ganoin, which has long been thought to be a type of enamel similar to that found on human teeth. The group's gene activity studies suggest that our teeth originated from genetic programs that formed protective scales in the skin of ancient armored fish.

The Nature Genetics paper was co-authored by 61 researchers from 33 institutions.