Mice Can Do Without Humans' Most Treasured Genes

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Mice Can Do Without Humans' Most Treasured Genes

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/05/080514124110.htm

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 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. "

The same thing happens in the mouse, but at a much later stage of

life, often past reproductive age. As a result, " many of these

vacuole proteins are not so 'essential' to the mouse, " Zhang

said. " Even without the proteins, the mouse can survive long enough

to reproduce. "

The researchers speculated that in the course of primate evolution,

as life span increased and reproductive age was delayed, efficient

waste management became increasingly important.

Additional results of their analysis support the idea. By developing

an index that incorporated metabolic rate (a measure of how fast

cellular waste products are generated) and reproductive age, and then

using that index to compare human and mouse, the researchers

determined that the total amount of waste produced per gram of body

mass from birth to reproductive age is about 18 times higher for

humans than for the mouse.

" Hence, waste management is much more important in humans than in the

mouse for maintaining proper cellular functions until the time of

reproduction, " Zhang said. " And when a biological process becomes

more important to a species, the genes involved in that process tend

to become essential. "

Zhang acknowledges that the study involved a relatively small number

of genes, and he hopes that other researchers will be able to confirm

the results as more information on human and mouse genes becomes

available.

" If our sample is unbiased, our results will have some important

implications, " he said. " First, in many genome projects, people draw

inferences about gene function by using information from other model

organisms. We need to be careful doing this because we now know that

a large fraction of the genes may have different functions or

different importance in different species. "

In addition, the results raise concerns about the widespread use of

mouse models for studying human disease.

" Our study does not say that mouse models are useless, " Zhang

said. " Even for those genes that have changed essentiality, the mouse

model may provide useful information. For example, it may tell us the

molecular function of the gene, even if the gene's importance differs

between species. But for some diseases, such as neurological diseases

related to vacuole proteins, the phenotype is so different that it

may be necessary to establish a primate model. "

The researchers received funding from the University of Michigan

Center for Computational Medicine and Biology, the National

Institutes of Health and the University of Michigan Rackham

Predoctoral Fellowship program.