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Surprises in the mouse genome

Like a mouse darting across the hearth and disappearing behind the home entertainment center, the mouse genome can surprise even the most seasoned geneticist. For Eugene Rinchik of ORNL's Life Sciences Division, the "unexpected discovery" has been a theme in his career of producing and studying mutant mice.

"We find a lot of wonderful surprises in this research," he says. For example, in the early 1990s, Rinchik and ORNL scientist Bem Culiat were studying a form of inherited cleft palate, a facial deformity and birth defect, in mice. They found that newborns affected with cleft palate were missing a certain neurotransmitter receptor gene. By adding a rat gene that codes for this neurotransmitter receptor to a fertilized mouse egg lacking the mouse gene, Culiat corrected the disorder, and the resulting mouse was born without a cleft palate.

"The 'surprise' was that a reasonable prediction for the function of this gene would not have included effects on the palate during fetal development," says Rinchik. "If we used only the known biochemical function of this receptor as a guide, we would expect to find neurological dysfunction, not cleft palate, as the primary defect."

In another example of surprising findings, Rinchik frequently tells audiences about four different genes in mice that encode proteins that share several structural characteristics. Computational gene modelers have classified these proteins as cell-signaling molecules. In general, such molecules instruct cells to divide, grow, step up their metabolism, or die, for example.

"Scientists have studied mice with mutations in each of these four genes," says Rinchik. "One mutant gene results in a defective protein that causes mouse embryos to die in the uterus. Another mutant causes mice to be born with cleft palates (for an apparently different reason than that discussed above). The third mutant results in inflammatory disease in young animals, and the fourth causes the mouse to be born with slight cartilage abnormalities that show up as shortened ears in an otherwise healthy animal.

"The point is that although these proteins belong to the same general family of cell-signaling molecules, they have different functions in the mouse. The evidence gained from mouse-breeding experiments improve understanding of what happens at the level of the organism and, therefore, add value to computational predictions about the biochemical functions of genes in the mouse genome."

Rinchik and his colleagues continue to look for new dominant and recessive single-base gene mutations in the descendants of mice exposed to ethylnitrosourea (ENU). He was inspired to use ENU by long-time ORNL geneticists Liane and Bill Russell, who pioneered its use for producing mouse mutants that could be models for human disease, making ORNL a world leader in this area. For example, recently, Rinchik was pleasantly surprised to find a new mouse mutation that could shed light on a human disease. Some of his mutant mice were found to have seizures continuously for a few weeks until they died.

These mice may be models for the human disorder epilepsy. The mice are currently being characterized by Lisa Webb, a graduate student working in Dabney Johnson's group at ORNL.

"Now that the DNA sequence of the mouse genome is being completed by the public sector, we should be able to locate and identify a mutated gene more rapidly," Rinchik says. "This can be done by comparing a DNA sequence with an altered base from a mutant mouse with the normal DNA sequence from the mouse genome map."

Rinchik sees more collaborations in the future between ORNL mouse geneticists and human geneticists. There is already a model for such interactions.

"In 1993, in a collaboration with Rob Nicholls, a human geneticist who is now at the University of Pennsylvania, we identified the human version of the mouse pink-eye dilution gene, which leads to a pigmentation defect in mice," Rinchik says. "Subsequently, human geneticists found mutations in this gene to be responsible for albinism in black Africans. They are born with little pigment and are light-skinned as a result."

Culiat, meanwhile, is using newly available molecular tools to explain a surprising finding by retired biologist Walderico Generoso. He found evidence suggesting that eggs from some female mouse strains can correct damage in sperm from male mice exposed to a toxic chemical, reducing the percentage of embryo deaths. By studying gene expression profiles, Culiat hopes to determine whether these eggs repair damaged DNA or have an extracellular filter that lets in normal sperm and keeps damaged sperm out. Indeed, the results could be surprising.

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