Taking lab mice back to their roots

When a laboratory mouse and a house mouse come nose to nose for the first time, each one is encountering something it has never seen before. They are both Mus musculus. But the wild mouse is facing a larger, fatter, calmer and less aggressive version of itself that’s the result of brother-to-sister inbreeding for generations, resulting in mice that are almost completely genetically identical.

Laboratory mice are incredibly valuable tools for research into diseases from Alzheimer’s to Zellweger syndrome. Scientists have a deep understanding of lab mouse DNA, and can use that knowledge to study how specific genes may control certain behaviors and underlie disease. But with all the inbreeding comes some traits that, while desirable in a lab mouse, may not reflect the behavior of an animal in the wild. So for some questions, and some behaviors, scientists might need something a bit wilder.

A new study takes lab mice back to their roots and along the way uncovers a new gene function. Lea Chalfin and colleagues at the Weizmann Institute of Science in Rohovot, Israel, bred laboratory mice with wild mice for 10 generations. The result was a mouse with wild mouse genes and wild mouse behavior — with a few important lab mouse genes mixed in. The technique allows scientists to place specific mutations in a wild mouse. The results have interesting implications for studying the mouse species, and might provide some new ways to study human disease as well.

Chalfin and her colleagues were especially interested in behaviors linked to female aggression. In lab mice, males are usually aggressive toward other males.  When a new male mouse enters the cage, the resident will do everything in his power to defend his turf. But female lab mice are much less aggressive. They can be put into a cage with other females without fights and will even nurse another mouse’s pups without complaint. Not so for wild mice. A wild female mouse can be very aggressive and will kill pups that are not her own.

“Lab mice can serve us a lot and answer many questions in medicine,” says Tali Kimchi, study coauthor and neurobiologist at the Weizmann Institute. “But for some questions, like aggression in females, they may not be the best model.”

The scientists focused on a gene called TrpC2 to explore the difference in aggression between the wild mouse and the lab mouse. TrpC2 should be important for pheromone communication between mice.  But in lab mice, TrpC2 appears to have no function at all.

To figure out the real function of TrpC2, the scientists caught wild mice in fields in Idaho and bred them in the lab to rule out any diseases. Then they bred the wild mice to lab mice with one of the pair of TrpC2 genes shut down. They did this experiment, called a back cross, for 10 generations, each time breeding the offspring with wild mice.

The result, published August 5 in Nature Communications, is a lab-bred mouse on the wild side. It’s slimmer, eats less and is more anxious than its lab counterpart. The breeding kept the TrpC2 gene mutation, with one of the TrpC2 gene pair rendered nonfunctional. Some of the new mice got two normal copies, and normal TrpC2. Others got altered copies, or had no TrpC2 function at all.

Like wild mice, the female “wild” lab mice were aggressive, attacking strange pups and other females. But while the female “wild” lab mice were aggressive, they were only aggressive if they had normal TrpC2. Those with the altered, nonfunctional TrpC2 lab gene were not aggressive. It turns out TrpC2 is an important gene for pheromone sensing and aggression in female mice, a function that was completely hidden in the docile female lab mice.

The results show that a gene that may have been disrupted during the domestication of the lab mouse could be crucial for natural mouse behavior. “Lab mice are easy to work with and breed, relatively cheap and there are powerful genetic models, behavioral paradigms and sequenced genomes at our disposal,” says Stephen Liberles, a cell biologist at Harvard University. “Their uniform genetic code also allows us to compare results from different researchers across the world.” But this study, he notes, “highlights the importance of considering the natural diversity of wild animal populations.”

This method could be useful for discovering the effects of other genes in wild mice, effects that might be hidden in a domesticated mouse. But the technique comes with some challenges. Wild mice and the “wild” lab mice, unlike inbred mice, do not all have the same genes, so behaviors in wild mice and lab-bred “wild” mice are going to be a lot more variable than they would be in a laboratory mouse, says Tsuyoshi Koide, a geneticist at the National Institute of Genetics in Mishima, Japan. Because of the huge variation in behavior in wild mice and in their lab-bred, genetically diverse bretheren, it is harder to figure out which behavior is typical to wild mice, and which is the result of many different genes affecting behaviors.

And in the end, it’s probably far too expensive and time-consuming to cross every gene you need back in to wild mice for 10 generations. Koide notes that while this paper support the “tremendous value” of wild mice, other methods for editing genes might be a better choice than an expensive back-cross.

But the paper also reveals that the female lab mouse has suffered far more behavioral changes during domestication than male mice. “It was quite striking to find most of the changes were in females,” Kimchi remarks. “We don’t know anything about the mechanisms behind female aggressive behavior, because in female lab mice, it’s just not there.” The new technique to bring wild traits back into the lab could help scientists understand more about aggression and other traits in female mice. In other words, to understand why mice behave the way they do, sometimes scientists need to go into the wild.