Researchers Identify Candidate Human Pheromone Receptor Gene

"We have shown that contrary to the prevailing notion in the field, the human genome contains at least one gene that encodes a candidate pheromone receptor," says Peter Mombaerts, M.D., Ph.D., assistant professor and head of the Laboratory of Developmental Biology and Neurogenetics at Rockefeller. Mombaerts led the research team, which included first author Ivan Rodriguez, Ph.D., and Mai Y. Mok, from the Laboratory of Developmental Biology and Neurogenetics at Rockefeller, and Charles A. Greer, Ph.D., professor of Neuroscience at Yale.

The gene, called V1RL1 (V1R-like gene-1), encodes a protein that shares amino acid similarity with the mouse and rat pheromone receptors.

Pheromones are essential chemicals used by individuals of the same species to communicate with each other, eliciting specific behaviors. In mammals, these chemical signals are detected in the nasal cavity by sensory neurons that express pheromone receptors. In rodents, these receptors belong to two large multigene families, called V1r and V2r. Although pheromonal effects have been demonstrated in humans - most notably the synchronization of the menstrual cycles of women living in close proximity - no human counterparts to the rodent pheromone receptor genes have been previously reported.

The researchers took a genomics approach and found eight different human sequences that resemble rodent V1r sequences. Seven of the sequences were determined to be "pseudogenes." A pseudogene looks like a gene, but is defective because it does not result in the production of an intact protein.

"Pseudogenes are typically an evolutionary vestige," says Mombaerts. "To other species, such as rodents, those genes may have been important for survival, but to us, they have become defective because there is no selective pressure to keep them intact."

"In mice, we think there are more than 100 functional genes in the V1r family," says Rodriguez, "but in humans, V1RL1 may very well be the sole functional V1r counterpart."

The researchers screened a wide range of human tissues to determine where V1RL1 gene expression takes place. They found expression consistently in the olfactory mucosa, which is used to detect smells, but not in most other tissues. Expression was detected in brain, lung and kidney, but not reproducibly, suggesting low expression levels in these organs, which may not be functionally significant.

The team looked at 11 individuals of varying ethnicities and found two forms of the V1RL1 receptor that differ by only two amino acids.

"In none of these people was V1RL1 a pseudogene, suggesting that evolutionary selection has maintained it in a functional state throughout the human species," says Rodriguez.

In rodents, pheromone detection is thought to occur mainly via the vomeronasal organ (VNO), a specialized sensory organ located at the base of the nasal septum. Surgical removal of the VNO has a dramatic effect on the social and reproductive behavior of rodents, particularly when performed at a very young age. The "V" of "V1r genes" refers to the expression of these genes in neurons of the rodent VNO.

"The nose of the newborn human harbors a cigar-like structure resembling a rodent VNO, but it regresses with time," says Greer. "A vestigial VNO is still left in some adult human beings, but little evidence exists that it is functional. We have been able to circumvent this anatomical conundrum by taking a novel approach strictly based on genomics."

Why is V1RL1 still present and functional in the human genome? The scientists do not know yet. "Our discovery could lead to novel products for consumers and patients," speculates Mombaerts.

The research was supported in part by the U.S. National Institutes of Health, the March of Dimes Birth Defects Foundation and Senomyx, Inc., a San Diego biotechnology company. Rodriguez was supported by postdoctoral fellowships from the Swiss National Science Foundation, the European Molecular Biology Organization and the Human Frontier Science Program.

Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the recent determination of the 3-D structure of the cellular RNA polymerase, a molecular machine that activates individual genes. The university has ties to 20 Nobel laureates, including the recipient of the 1999 Nobel Prize for Physiology or Medicine, Günter Blobel. Thirty-two faculty members are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D.