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Survivor in the human genome
Proposed human pheromone receptor is expressed in olfactory tissue
Edward R. Winstead

Somehow, the notion that humans don't have any pheromone receptor genes came to be conventional wisdom in the scientific community. And that notion may turn out to be true. But this week a team of researchers announces that the human genome contains at least one gene that closely resembles a family of mouse pheromone receptors—genes that are primarily involved in detecting odorless chemicals such as pheromones. These chemicals are the signals of a 'second' olfactory system in many species: the release of pheromones by one individual, for example, can trigger sexual behavior in another individual. The proposed human pheromone receptor is expressed in the main system of smell in humans, according to the researchers.

If the gene really was a pheromone receptor, what is it doing now?

"We took a molecular approach and asked whether any aspects of a pheromonal system are preserved in the human genome," says Peter Mombaerts, of The Rockefeller University in New York. Two years ago, his laboratory identified eight human DNA sequences that share distinct structural elements with mouse pheromone receptors. Seven of the sequences proved not to be functional genes. One sequence, however, encodes a receptor protein found in epithelial tissue in the nasal cavity. The findings appear in the September issue of Nature Genetics.

For decades, studies have found physiological evidence of pheromonal effects in humans, most notably the synchronization of menstrual cycles of some women who live together. In 1995, the discovery of pheromone receptor genes in the mouse sparked new interest in these genes in humans. No one has been able to demonstrate that humans have an accessory, or vomeronasal, olfactory system. The organ that mediates 'unconscious' chemical communication in mice is essentially a vestigial shell in adult humans. The structure, the vomeronasal organ, or VNO, was first described in 1813 by the Dutch anatomist Ludvig Jacobson and is commonly referred to as Jacobson's organ.

Turning to the genome for evidence

The fact that the VNO is vestigial in adulthood doesn't preclude the survival of vomeronasal receptor genes. Convinced that the conventional wisdom about these genes was not based on any hard evidence, Mombaerts began searching the human genome for evidence of an accessory system of smell. In the mouse, vomeronasal receptors are structurally distinct from odorant receptors in the main olfactory system, suggesting that human counterparts would be recognizable. By 1998, it was clear that mice have more than 100 vomeronasal receptor genes, comprising two gene families, V1r and V2r.

When the search began, a relatively small amount of human sequence data was available. The researchers used the mouse data and a combination of traditional gene-hunting techniques to find the eight human sequences. The proposed gene, which is called V1RL1 (V1r-like gene-1), resides on chromosome 19. The gene has been present in public databases for some time, and Mombaerts admits that his group initially did not recognize the sequence as a receptor candidate.

With the sequence in hand, the researchers analyzed DNA from an ethnically diverse group of 11 individuals and found two forms of the V1RL1 gene, each with a slightly different structure. Mombaerts doesn't rule out the possibility that more pheromone receptors will turn up in sequence data in the future, but he is confident that only a few more, if any, will emerge.

Expression studies

To determine where in humans the V1RL1 gene is expressed, Mombaerts teamed up with Charles Greer, who directs the Neurosurgery Research Laboratories at Yale University. The researchers screened a variety of human tissues and detected low levels of activity in the brain, lung and kidney. That activity, says Mombaerts, was not unexpected and is probably insignificant. More important, he consistently found expression of V1RL1 in the olfactory mucosa, which is involved in scent detection. The specific types of human cells that express the gene have not been identified, in part because of the technical challenges involved.

If V1RL1 really is a vomeronasal receptor, how did it end up in the main olfactory system? The question cannot be answered, of course, but natural selection may be to blame. "Genes survive or they don't survive," says Greer. "One possible explanation is that this receptor is better at detecting chemicals than was a gene in the olfactory epithelium."

"Until this report," Greer continues, "the consensus was that humans do not have receptors that belong to this family of genes. Now the door is open to reconsidering the functional organization of the human olfactory system." Studies in pigs and rabbits have found that the two olfactory systems are probably not completely separate entities. Pigs that lack a functional VNO can detect pheromones through the main olfactory system, for example.

An ‘Autobahn’ of possibilities

"This is a pivotal study," says Charles Wysocki, of the Monell Chemical Senses Center and the University of Pennsylvania. "The new avenues it opens are like an Autobahn: People will ask questions that would not have been asked otherwise, and these are questions that people can actually do something about." He notes that studies are underway to characterize the VNO and accessory olfactory systems in great apes.

Wysocki wants to know if this gene is present in the main system and/or the accessory system of a variety of mammals, especially animals like dogs and horses. If V1RL1 is present only in the accessory system of animals that have both systems, then one might conclude that the gene somehow migrated to the main system in humans, he says. It would suggest that V1RL1 "is probably very important and is finding a way to get expressed."

The Nature Genetics paper doesn't address the question of whether humans have a vomeronasal system, which is where one would expect to find this gene, notes Wysocki. He also disagrees with Mombaerts' use of the term 'pheromone receptor' because it implies that more is known about pheromones and the vomeronasal and main olfactory systems than actually is. "Animals can respond to pheromones using the main olfactory system," he says, "so to make an equivalency between the VNO and pheromones is a false equivalency."

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Rodriguez, I. et al. A putative pheromone receptor gene expressed in human olfactory mucosa. Nat Gen 26, 18-19 (September 2000).

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