Deleting a gene region previously associated with autism can cause mice to exhibit autism-like behaviors and brain changes. The findings, published in the Proceedings of the National Academy of Sciences today (October 3), suggest that at least some of the genes in that region may play a role in a small percentage of autism cases in humans, and could be the basis for new mouse models of autism.
“The nice thing is we now have, for the first time, an experimental pathway in the mouse to try to narrow which genes are important [in autism] and which genes are not,” said cancer biologist Arnold Levine at the Institute for Advanced Study in Princeton, New Jersey, who was not involved in the work.
Since 2007, researchers have noted that patients with autism had a number of copy number variants—duplications or deletions of large gene regions that likely occur during...
Geneticist Alea Mills of Cold Spring Harbor Laboratory in New York and her colleagues investigated one particular region, called 16p11.2, which encodes about 27 genes, and has been associated with autism in a couple dozen patients. The researchers deleted this gene region in one group of mice, while another group received a duplication of the region.
Roughly half of the mice who had the 16p11.2 deletion died shortly after birth, though the researchers couldn’t find any developmental differences to explain this higher mortality.
The surviving mice in the deletion group were healthy, but displayed some very odd behaviors. “It was so striking,” Mills said. “You could tell they were very, very different.” They were hyperactive, compulsively groomed themselves, and hardly ever slept. In a ceiling climbing behavioral test, they never learned new ways to get down from the ceiling, unlike wild-type mice. Many of these traits are reminiscent of autism in humans, Mills said.
autism.vs.control.movie2When the researchers looked closely at the brains of a subset of these mice under MRI, they found changes in several regions of the brain were enlarged.
In contrast to the consequences of a deletion, duplications cause reciprocal, and much less severe, changes in the mice’s behaviors and brains: they slept too much, and didn’t like to climb the ceilings at all. And these mice had smaller brain regions as compared to wild type. The findings hint that some of the genes in the 16p11.2 region could be responsible for some autism behaviors in humans, and that the effect of deletions or duplications may be opposing, Mills said.
But even if researchers could narrow down the actual genes linked to autism in this case, it would only account for a tiny percentage of autism diagnoses, since the overwhelming majority of patients do not have this particular copy number variant, Levine said.
The new approach could theoretically be used to develop new mouse models of autism, Levine said. But in order to do so, researchers would need to develop tests to provide greater clarity regarding the animals’ autism-like traits, he added.
A more immediate implication of the research may have to do with neonatal deaths. Because half of the deletion mice died, the researchers wonder whether the tissue from some babies who die of unexplained causes could be examined to see whether a similar deletion plays a role in those deaths, Mills added.
“There’s all these descriptions of kids who fail to thrive after birth and they don’t know why,” Mills said. “If what we found in the mouse extends to humans that would be important.”
G. Horev et. al, “Dosage-dependent phenotypes in models of 16p11.2lesions found in autism,” Proceedings of the National Academy of Sciences, doi/10.1073/pnas.1114042108, 2011.