The Sciences

Speak, Mouse

By Carl ZimmerMay 28, 2009 11:01 AM


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More and more, scientists are figuring out the molecular changes that have taken place over the course of our evolution. It's one thing, however, to have a good idea of the ways in which our DNA was altered, but it's quite another to figure out how those changes affected our ancestors, and how those changes may have spread from an individual to the entire species through a process such as natural selection.

Knowing how genes work makes it possible to come up with hypotheses about how changes to those genes evolved. And today scientists can engineer animals to see if those hypotheses hold up. A couple years ago I blogged about a study on the evolution of our color vision, in which scientists gave mice the power to see the colors that we (and other primates) can see. Now comes a similar study on the evolution of language. The mice involved may not be able to talk, but their brains have changed in some very interesting ways.

This story begins with a family in London who had trouble with language. Some members of the family had trouble speaking and understanding grammar. They turned out to have an inherited language disorder, and scientists were able to use the family's genealogy to pinpoint the gene involved, which they dubbed Foxp2. Foxp2 encodes a transcription factor, a protein that switches other genes on or off. That can make a gene very powerful, but it can also make it hard for scientists to figure out what it does, since its ultimate effects on a person's body must first be carried down through a cascade of other genes. But it's pretty clear at this point that Foxp2 influences the development of the brain.

Foxp2 exists in other animals, and in many cases it appears to have an influence on communication. When scientists have knocked out the gene in mouse embryos, for example, the mice are born having trouble producing the ultrasonic squeaks they need to make in order to get help from their mother. In 2002, Wolfgang Enard of the Max-Planck Institute for Evolutionary Anthropology and his colleagues compared the version of Foxp2 in humans to other animals and found that it had undergone a dramatic evolution in our own ancestry after our ancestors branched off from those of chimpanzees and bonobos. Our hominid ancestors aquired two mutations to the gene that each changed an amino acid in the Foxp2 protein. In 2007, Max Planck researchers announced that they had found the Foxp2 gene in the DNA of Neanderthals, our closest hominid relatives. It turned out they shared that same altered sequence. If Neanderthals share our version of Foxp2 thanks to common descent, that means that the two amino acids changed before our common ancestors split off, some 800,000 years ago. It presumably was one of many changes that took place to many genes in our hominid ancestors on the road to full-blown language.

To get a sense of how this new version of Foxp2 might have changed the brains of our ancestors, Enard and his colleagues have now tweaked Foxp2 in mice into a human form. Because Foxp2 has changed very little in mammal evolution (except in humans), a mouse version of Foxp2 is a fairly good model for what the gene looked like in our own ancestors. And so this experiment can, in very rough form, replay the transition from the old Foxp2 to the new.

As the scientists report in Cell tomorrow, the mice are generally healthy, but their behavior has changed. Their squeaks are lower in frequency. They explore less. They have less dopamine in the brain, a neurotransmitter that we need to control our bodies and to pursue rewarding things like food. Dopamine is produced in the base of the brain by a clump of neurons called the basal ganglia.

Scientists who have studied people with Foxp2 defects have noticed that part of the basal ganglia, called the striatum, is altered. So the researchers looked closely at the striatum of the humanized mice. They discoverd that certain kinds of neurons had longer branches and could sprout new connections with other neurons than in regular mice.

None of these changes should be accepted blindly as having happened in our own ancestors. The effect of a mutation to a gene depends a lot on the other genes it interacts with. When Foxp2 changed in our ancestors, it was interacting with many other hominid genes, not with genes in mice.

Nevertheless, there are many intriguing clues from this study that hint that perhaps these mice are pointing to at least a few changes that gave rise to language. It turns out, for example, that people who produce less dopamine in the basal ganglia do a better job of breaking down the sounds of speech into smaller chunks in the brain in order to undertand the words someone is saying. It's also intriguing that songbirds have independently evolved Foxp2 as they've become excellent singers, and when scientists block Foxp2 expression in the basal ganglia of birds, they do a worse job of singing.

Obviously, mice are no better at singing like birds than they are at talking like us. But it's possible that their brains have been tweaked in a crucial way, much as happened independently in the ancestors of both birds and people.

Source: Enard et al.: “A Humanized Version of Foxp2 Affects Cortico-Basal Ganglia Circuits in Mice.” Cell 137, 961–971, May 29, 2009. DOI 10.1016/j.cell.2009.03.041 www.cell.comPublishing in

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