Mouse can do without man's most treasured genes

ANN ARBOR, Mich.---The mouse is a stalwart stand-in for humans in medical research, thanks to genomes that are 85 percent identical. But identical genes may behave differently in mouse and man, a study by University of Michigan evolutionary biologists Ben-Yang Liao and Jianzhi Zhang reveals.

Their results, which have implications for the use of mouse models in studying human disease, appear in the current issue of the journal Proceedings of the National Academy of Sciences (PNAS).

"Everyone assumes that deletion of the same gene in the mouse and in humans produces the same phenotype (an observable trait such as presence or absence of a particular disease). That's the basis of using the mouse to study human disease," said Zhang, an associate professor of ecology and evolutionary biology. "Our results show that may not always be the case."

Zhang and his graduate student Liao focused their study on so-called essential genes---genes which, through their effects on survival or fertility, are necessary for organisms to reach sexual maturity and reproduce. They then homed in on 120 essential human genes for which the mouse has an identical counterpart that also has been studied. Next they consulted a database that catalogs the results of experiments in which the mouse equivalents of human genes are deleted, or "knocked out."

If those 120 essential human genes are also essential in the mouse, deleting any of them should result in infertility or death before reproductive age. But the database showed an unexpected discrepancy.

"To our surprise, 22 percent of the 120 human essential genes are nonessential in the mouse," Zhang said. "I expected there would be some, but I never expected the percentage to be so high."

Intrigued, the researchers wanted to understand why the "essentiality" of some genes has changed in the time since human and mouse last shared a common ancestor. Looking more closely at the protein products of the individual genes that are essential in humans but nonessential in the mouse, they discovered that a much higher than expected percentage are located in the vacuole, a sac-like cellular structure that functions as a garbage dump---but a highly important garbage dump.

"The main function of the vacuole is to contain and degrade cellular wastes and toxins," Zhang said. "In humans, the absence of vacuole proteins causes those wastes and toxins to accumulate, often leading to fatal neurological diseases."