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Flaws in the Mouse Model?

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Today in Mice owes its existence to the practice of using model organisms — that is, rodents — to study human biology and diseases. Because mice share 85 percent of their genome in common with humans, the thinking has been that using these distant, furry cousins of ours in research can help scientists predict disease processes in people.

The operating assumption has been that removing the equivalent (or orthologous) gene from mice and from people will create in the two species comparable phenotypes, or the observable properties of the organism, including diseases. Evolutionary biologists at the University of Michigan have discovered, however, that more than a fifth of the 120 genes that are considered essential in humans — that is, those that enable us to live to adulthood and reproduce — are not essential for mice.

The difference, say researchers Ben-Yang Liao and Jianzhi Zhang, may be linked to the human animal's advanced waste management capabilities, an adaptation resulting from the longer life span and later reproductive age associated with primates. With their research showing that humans produce 18 times more waste than mice per gram of body mass from birth to puberty, Zhang points out, "Waste management is much more important in humans than in the mouse for maintaining proper cellular functions until the time of reproduction. And when a biological process becomes more important to a species, the genes involved in that process tend to become essential."

Mice, by contrast, even when the genes that produce the proteins that aid in waste management have been deleted from their genotype, "can survive long enough to reproduce," says Zhang.

The researchers aren't ready to toss out the mouse model altogether, but they do warn that disparities in the phenotypes resulting from changes to orthologous genes should make scientists cautious about drawing conclusions about genes and phenotypes across species, even closely related ones. "For some diseases," says Zhang, "such as neurological diseases related to vacuole [waste-degrading] proteins, the phenotype is so different that it may be necessary to establish a primate model."

Does that mean we'll be starting a Today in Mandrills blog? You read it here first.