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Nose to nose with genetic families

Janet Young, others in Trask lab, examine olfactory receptors of mice, humans
Dr. Janet Young uses a phylogenetic tree to explain to research technician Joe Ross
Dr. Janet Young uses a phylogenetic tree to explain to research technician Joe Ross the evolutionary relationship between olfactory receptor genes in mice and humans. The two work in the lab of Dr. Barbara Trask, director of the Human Biology Division. Photo by Michelle Hruby

Mice aren't known to snub Velveeta in favor of a fine French Brie. Yet new genome research suggests that a rodent's nose could be far more discriminating than that of a cheese connoisseur at a four-star restaurant.

Humans dedicate about 350 functional genes to olfaction, the perception of odors as distinct as a bouquet of roses or a manure-fertilized pasture. But mice have triple that - more than 1,000 such olfactory-receptor genes, said Dr. Janet Young, a postdoctoral fellow in Dr. Barbara Trask's laboratory in the Human Biology Division.

Young and colleagues recently completed a side-by-side comparison of these enormous gene families in mice and humans, a project made possible by the completion of both organisms' genome sequences. Their findings, which reveal clues to the evolutionary origins of these gene families, appeared as the cover story in the March 1 edition of Human Molecular Genetics.

Given most animals' reliance on odor perception for food acquisition and mating, the devotion of about one-30th of the mouse genome to this sense is not wholly surprising.

Expanded repertoire

Still, it's not clear what enhanced function is provided by this expanded repertoire of olfactory receptors, Young said.

"What we don't know yet is whether these additional genes enable mice to detect more things or just provide them with an enhanced ability to discriminate among related odorants," she said.

Olfactory-receptor genes contain the blueprints for proteins made in nerve cells found in the olfactory epithelium, the region of the nose that perceives smell.

Although smell may evoke powerful and complex memories and sensations, an odor is nothing more romantic than a volatile chemical or a mixture of more than one. Olfactory receptors bind to such chemicals and relay the input to the brain.

Each olfactory neuron produces one olfactory receptor, and each olfactory receptor interacts with a different subset of chemicals, an observation made by Dr. Linda Buck of the Basic Sciences Division. Because of this, the odorant-binding portions of an olfactory receptor must be unique to interact with only a few specific odorants. Other portions of all olfactory receptors - mouse or human - are similar in sequence.

Such blocks of similarity are what enabled Trask's group to comb the mouse-genome sequence to identify members of the olfactory-receptor family, Young said.

Highly conserved bits

"All of the olfactory-receptor genes are at least 40 percent identical to previously discovered olfactory receptors," she said.

"There are highly conserved bits of these molecules dedicated to transmitting signals to other proteins. After many computer hours, this similarity led us to the mouse genes."

From this analysis, Trask's lab concluded that the mouse genome harbors some 1,500 olfactory-receptor genes, although about 300 of those genes are probably nonfunctional "pseudo-genes," copies of true genes with mistakes that prevent the receptor from working.

In contrast, humans have about 900 olfactory-receptor genes, of which nearly two thirds are nonfunctional.

To determine evolutionary relatedness between the olfactory-receptor genes from each organism, Young tried to cross-match each mouse gene with a human counterpart.

"Most mouse olfactory-receptor genes had a gene in a comparable position in human genome," she said. "They must have been present there from when the two genomes diverged."

For many genes, particularly those involved in basic metabolic functions, Young said, humans have the same number of genes as mice, and the sequences of these genes are about 80 percent identical.

"But we find a lot of differences in gene families that are involved in recognition of external signals, such as olfactory-receptor genes and genes that play a role in the immune system," she said. "We find many extra olfactory-receptor genes in mice that humans do not have, and vice versa."

Young noticed unusual differences in how olfactory-receptor genes in mouse and humans are organized on chromosomes.

Some human olfactory genes are found in large blocks of sequences with similar copies on other chromosomes, whereas few mouse olfactory-receptor genes are part of large duplicated blocks.

Scientists presume that these blocks arise when chromosomal segments duplicate through a process called genetic recombination.

Recombination can also cause portions of DNA between similar regions to loop out and be deleted, which may result in the loss of important genes. Because the blocks containing olfactory receptors are so similar, researchers have identified examples of such deletions occurring between them, in one case resulting in a form of mental handicap, along with other medical problems. That makes the dynamics of the olfactory-receptor gene family a double-edged sword, Trask said.

Genome at risk

"The genome duplications result in expanded function, but, at the same time, they put the genome at risk for rearrangements that have deleterious consequences," she said.

Trask's group also determined that many of the analogous genes in mouse and humans contain enough differences in DNA sequence to potentially affect their functions.

"Even just a few changes in sequence of an olfactory receptor can change the type of odorant that it binds," Young said. "This means we might not be able to draw easy comparisons between the mouse and human genes."

Young said that this study provides a foundation to learn how this large gene family is regulated.

"Data we've generated will be useful to researchers who are looking at looking at how olfactory receptors are turned on or off in an individual neuron," she said.

"There are about 10 million neurons in the olfactory bulb, yet each neuron somehow selects only one olfactory receptor to use. We hope to begin to understand how this happens."



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