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Scents and Pheromones
Mice have a thousand genes for detecting a world of odors
By Adam Marcus

Featured article.

Two scientists have identified more than a thousand genes in mice dedicated to perceiving smells. Rodents, we now know, have many more genes for smell than humans do, a trait that may give them a greater entrée to the world of odors. In a related finding, scientists say the repertoire of pheromone genes in mice is larger than expected. Pheromones are chemical signals that mice and other species use to send and receive information about everything from aggression to love.

More genes in humans and mice are devoted to perceiving odors than to any other single purpose. The abundance of these genes—olfactory receptors (ORs)—underscores the importance of smell to most mammals. Mice are widely used in the laboratory to study smell, and the new data could lead to new understandings of human and animal behavior, enhance the pleasures of eating, and, yes, even help build a better mousetrap.

"This is the largest gene family that we know of in the mammalian genome," says Stuart Firestein, of Columbia University in New York, who led the study. He and a colleague, Xinmin Zhang, developed algorithms to sift through a draft of the mouse genome sequence released in May 2000 by Celera Genomics in Rockville, Maryland. The algorithms turned up nearly 1,300 OR genes.

‘We'd like to use olfactory cues to modify the behavior of pest animals.’

Olfactory receptor genes encode proteins that reside on nerve cells in the nasal passages and bind chemicals in the environment. When the binding occurs, a message is sent to the brain, reporting the presence of odors ranging from blue cheese to rose attar.

Soon after the human genome was sequenced, researchers identified about 900 human OR genes. But two-thirds of these turned out to be nonfunctional, or 'pseudogenes' that have fallen into disuse along evolution's way. The Columbia researchers found that the OR genome in mice has far fewer pseudogenes—only about twenty percent of the total. Thus, mice appear to have preserved more functional OR genes than humans.

The conventional wisdom among researchers seems to be that mice are more sensitive to a broader array of odors than humans. Firestein and Zhang suggest that humans do just fine with fewer receptors. "The human olfactory system has probably retained the ability to recognize a broad, if perhaps less discriminating, spectrum of chemicals while using one-third the number of ORs as in mouse," they write in the current issue of Nature Neuroscience.

In recent years, researchers have laid out the OR genomes of both the fruit fly and the soil worm. But these species may be less relevant models of human olfaction than some researchers would hope. The genes of flies and worms "are quite different in sequence—and probably in structure—from the mammalian genes," notes Firestein.

Detail from phylogenetic tree of human and mouse ORs. View larger

Fish, it turns out, may be a model of a sort. Firestein and Zhang found a group of fish-like olfactory receptors embedded in the mouse genome. Fish perceive compounds that are soluble in water such as alcohols and acids, while mammals mostly detect molecules that float in gasses, like vanilla extract. Although the role of fish-like ORs in mice is not clear, they may help rodents detect water-soluble compounds.

Humans have fish-like receptors as well. "The working assumption is that these receptors are particularly good at detecting the more soluble types of odors," says Firestein. "They may be important for tasting food, such as meaty flavors and fatty acid."

Making one-to-one comparisons between olfactory receptors in humans and mice is tricky because similar receptors may bind different odorants, according to Barbara J. Trask, of the Fred Hutchinson Cancer Research Center in Seattle. Her laboratory recently completed a comparison of the mouse and human olfactory genomes. Most of the same subtypes of OR genes are present in both species—probably the legacy of a common ancestor. But local duplications in each genome have expanded and revised the repertoire of genes.

The additional OR genes in mice raise interesting questions. "Do they make mice more sensitive to the same molecules they have always detected?" asks Trask. "Or have slight variations in the receptors allowed rodents to recognize new aromas?" Put another way, do modern mice discern Vermont from Canadian cheddar whereas their forbearers could only find Havarti in a haystack?

Asking questions about olfactory systems is easier than answering them. Olfactory receptors are buried in the nasal cavity, making it nearly impossible to monitor in vivo the activation of a single receptor. As in any neurological study, researchers face a technical challenge in trying to understand how olfactory information is represented in the brain.

A major puzzle of olfaction is the regulation of receptor genes. In the olfactory system, individual neurons express one receptor gene out of a thousand. Each receptor binds a narrow range of odorants; it is only by having so many collective neurons that the system can detect and distinguish a world of smells.

Schematic of sequence conservation in the mouse V1r superfamily. View larger

"The olfactory system is organized around a daunting regulatory problem," says Robert P. Lane, a colleague of Trask's at the Fred Hutchinson Cancer Research Center. "When there are large numbers of olfactory genes in all corners of the genome, how does each sensory neuron restrict its expression to only one olfactory receptor?"

Lane is investigating the question by analyzing olfactory regions of the human and mouse genomes. The project aims to identify elusive regulatory mechanisms by discovering DNA sequences near OR genes common to both species. He recently reported findings from the comparison in Genome Research, but the question has by no means been resolved.

Olfactory receptors belong to a class of ubiquitous proteins called G protein-coupled receptors (GPCRs). In humans, these molecules are found in the brain, where they interact with neurotransmitters like serotonin and dopamine; they are in the eyes, the heart, the blood vessels, the gut. And they are in the laboratory.

"Something like 50 percent of all drugs on the market—or in the pipeline—target GPCRs," says Firestein. Creating drugs to interact with specific GPCRs, however, is time consuming and expensive. The new data on mouse OR genes could prove useful in the development of such drugs. The mouse olfactory genome is a kind of natural experiment, and now researchers have the genetic code for 1,300 receptor proteins.

Drug design is one use for olfactory information. Rat control is another. Firestein and two colleagues are forming a company to design anti-pest chemicals. "We'd like to use olfactory cues to modify the behavior of pest animals," says Firestein, citing New York subway rats as potential targets. The chemicals could be custom-crafted repellents to drive away benign nuisances or alluring scents to draw pests into traps for removal.

Schematic of pheromone system and gender discrimination. View larger

Such chemicals already exist in nature; they are called pheromones. In a related study published in the same issue of Nature Neuroscience, researchers have discovered more than 100 novel pheromone receptor genes in mice. These receptors are presumptive docking stations in rodents for pheromones, the elusive self-scents that species use to communicate.

A team led by Peter Mombaerts, of The Rockefeller University in New York, used Celera and public data to identify 137 functional pheromone receptors of a particular type (out of 293 candidates). Just a few years ago, mice were thought to have approximately 100 pheromone receptor genes. It is not clear why mice have so many receptors when researchers know of so few behaviors—about a dozen at last count—that are directly linked to the pheromones.

Courtship and mating in the animal kingdom have long been associated with pheromones. A new study in mice supports this notion by showing that male mice lacking a pheromone receptor gene attempted to mate with other male mice. The researchers had deleted the gene for the pheromone receptor protein TRP2 (for Transient Receptor Protein), which resulted in the abnormal behavior. Usually, male mice are territorial and become aggressive around other males.

A major function of the pheromone system, the researchers conclude, is to provide the brain with necessary cues for sexual discrimination, which ensures that males select females as mates. Even when the researchers reinforced the smell of male mice by splashing them with urine—which contains pheromones—the genetically modified males attempted to mate, apparently unable to respond to the signals.

"Although most of the pheromones emitted by the mouse remain chemically unidentified, our data suggest that they are not simple 'releasers' of motor programs but that they act, at least in part, as regulators of inputs from other sensory organs," the researchers write in Science Express. Catherine Dulac, of Harvard University in Cambridge, Massachusetts, led the study.

The human genome contains genes that closely resemble pheromone receptors in mice, but the existence of pheromones in humans has yet to be proved.

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Rodriguez, I. et al. Multiple new and isolated families within the mouse superfamily of V1r vomeronasal receptors. Nat Neurosci 5, 134-140 (February 2002).
Zhang, X. & Firestein, S. The olfactory receptor gene superfamily of the mouse. Nat Neurosci 5, 124-133 (February 2002).
Stowers, L. et al. Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science Express. Published online January 31, 2002.
Lane, R.P. et al. Genomic analysis of the olfactory receptor region of the mouse and human T-cell receptor a/d loci. Genome Res 12, 81-87 (January 2002).

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