Pioneering Genome Analysis Reveals the Genes Responsible for Pheromonal Communication Among Rodents

Research among the first published analyses of Celera mouse genome database

Rockefeller University scientists report that the way mice communicate with each other is far more complex — and has a more elaborate evolutionary history — than imagined.

The research, published in the February issue of Nature Neuroscience, provides the first global draft of an entire superfamily of genes thought to be involved in pheromone perception, a process critical to survival of animal species.

Rodents get much of their information about the world through their sense of smell. They use their noses not only to find or avoid certain foods but also to interpret chemical “messages,” such as mating pheromones, that are secreted by other members of the same species. Rodents use two different, specialized systems to interpret smell: the main olfactory system, which senses common odorants like food, and the vomeronasal system, which detects chemical cues related to intraspecies communication.

As Rockefeller Associate Professor Peter Mombaerts, M.D., Ph.D., and his colleagues discovered in 1999, the “wiring diagram” of the vomeronasal system is much more complex than that of the main olfactory system. This is likely because pheromones are a “cocktail” of chemicals rather than a single odorant. When the vomeronasal organ is surgically removed from animals, they undergo profound changes in behaviors like mating and aggression.

To pinpoint the genes involved in this crucial system, Mombaerts and his Nature Neuroscience co-authors used an algorithmic analysis to sift through the nearly complete mouse gene databases, mostly of Celera Genomics and also of the public genome project. The scientists cataloged an important group of candidate pheromone-receptor genes in the vomeronasal system: the V1r superfamily, of which the first members were discovered in 1995.

The researchers followed three criteria for classifying genes in this particular superfamily: general sequence homology, as well as the appearance of certain stretches of amino acids that form a “signature” for a particular family; the length of particular segments that usually vary little within a family; and the putative functionality of the receptors.

By searching for all genes that met these characteristics, the researchers were able to identify 104 new V1r genes and eight new V1r families, bringing the total to 137 V1r genes in the mouse genome.

The scientists were surprised to find that the V1r superfamily appears to be highly diverse: the eight new gene families are extremely isolated genetically from one another, as well as from the four previously identified families.

“That is probably why they remained undiscovered so long, and highlights the power of genomics,” says Mombaerts.

To Mombaerts and his colleagues, it appears that an original array of vomeronasal genes changed over evolution when some genes were duplicated and others lost.

But why such an extreme degree of diversity in the V1r repertoire – and why so many receptors?

“We propose three explanations, which need not be mutually exclusive,” explains first author Ivan Rodriguez, Ph.D., a former postdoctoral researcher at Rockefeller who is now an assistant professor at the University of Geneva in Switzerland. “First, it is possible that a repertoire of this size is required to discriminate between secretions of one’s own species and those of related species. A second, and very testable, hypothesis, is that the evolution of such a large and diverse V1r family is driven by some other, non-pheromonal function of some V1r genes, although they would still be involved in behavioral responses. The third hypothesis is that the complex and diverse repertoire may simply reflect the remarkable ability of its members to amplify throughout the genome.”

Mombaerts and Rodriguez’s co-authors are graduate student Karina Del Punta and postdoctoral fellows Andrea Rothman, Ph.D., and Tomohiro Ishii, Ph.D.

This research was supported by the Swiss National Foundation for Research, U.S. National Institutes of Health, Charles H. Revson Biomedical Research Foundation and the March of Dimes.