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SCIENTIFIC RESEARCH Gene mutations pacify mice, possibly humans



Published: Thu, July 7, 2005 @ 12:00 a.m.



Research findings show decreased violence directly related to the NR2E1 gene.

TORONTO GLOBE AND MAIL

A breakthrough experiment has used a human gene to turn vicious mice into very gentle creatures -- holding out the prospect of doing similarly sweet things to violent people.

Scientists at the University of British Columbia's Center for Molecular Medicine and Therapeutics created a strain of extremely vicious lab mice three years ago after accidentally deleting a gene that affects brain development.

The mutant mice were so aggressive they killed their mates, chewed their siblings' tails and even attacked their lab handlers.

The unanswered question was whether the human form of the gene also plays a role in aggression in people. The new research now suggests that it does. By giving mutant mice embryos the human version of the gene they were missing, the UBC team found the nasty rodents grew into a rather nice strain instead.

As such, the experiment raises the possibility of designing a gene therapy to counter aggression -- as well as the eerie specter of enhancing it.

Human link

More immediately, it means mice can act as models to study human genes involved in abnormal behavior and psychiatric disorders.

"Mice have been used to study human genes for cancers and other diseases lots," said UBC geneticist Elizabeth Simpson, senior author of the report published Wednesday in the Journal of Neuroscience. "But this is the first time [a human gene] is being used in a mouse to study the brain and behavior."

After UBC researchers created the so-called "fierce mice" in 2002, they searched the human genome looking for a gene with a sequence that closely matched the one missing in their mutant mice.

That gene, Simpson said, called NR2E1, is found on a region of Chromosome 6 in humans that has been repeatedly associated with bipolar disorder, a serious medical illness resulting in dramatic mood swings. The gene itself produces molecules that regulate other genes, suggesting it plays many roles in the human body, including those involved in brain development and function. That a similar version exists in the mouse suggests the gene is a primitive one, passed down to mice and people from a common ancestor many millenniums ago. The team ordered the human gene by mail and then inserted it into a mouse embryo at the earliest stage of development. This way the new human gene would be absorbed into the animal's genome as the embryo cell divided and grew.

Results

Mice without any form of the NR2E1 genes were, as predicted, violent. Those with two copies of the mouse gene were normal, as were those with one mouse copy and one human copy. But most surprising was that mice that carried only the human NR2E1 gene also appeared to be normal.

"They were indistinguishable from mice in the wild," Simpson said.

The researchers also were careful to control for environmental forces that could result in different behaviors, feeding all strains the same food, in the same kinds of cages and offering them the same social interactions: "The only thing that differed in these mice was their genetic constitution."

University of Lethbridge neuroscientist Bryan Kolb, who studies early brain injuries in rats, said the experiment amazed him.




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