A human gene makes mice squeak differently — did it contribute to language?

A gene variant present in most people might have contributed to cognitive differences between humans and their closest relatives

Almost all humans carrying a gene variant called *NOVA1* that is not present in ancient human relatives and has been implicated in the development of speech.Credit: 10'000 Hours/Getty

Mice carrying a gene variant present in nearly every human on Earth — and not by extinct relatives including Neanderthals — produce more complex chirps than normal rodents¹.

The finding suggests that the mutation — which changes a protein called NOVA1 that has a role in orchestrating gene activity in the brain — might have contributed to cognitive differences between humans and their closest relatives, and possibly to aspects of complex speech and language.

Robert Darnell, a neuroscientist at Rockefeller University in New York City, first encountered the NOVA1 gene 30 years ago, when his team linked it to an autoimmune disorder that caused severe movement problems in people. The gene is usually switched on only in the brain where the NOVA1 protein controls the expression of dozens of other brain-active genes.

Darnell thought that NOVA1 might be involved in speech when, as a neurologist, he treated a boy with language and movement problems, who had one working copy of the gene². Another team had found that nearly all humans have a version of NOVA1 that is distinct from Neanderthals and another extinct human group called Denisovans (as well as other mammals, including mice)³.

Chirp change

The genetic change — which swaps an isoleucine amino acid for a valine in the encoded protein — was one of just a handful of protein-altering changes that evolved in the more than 500,000 years after the hominin groups split from a common ancestor in Africa. This suggests that the changes benefited early humans so greatly that the mutations became ubiquitous.

To study the effects of the change a neuroscientist in Darnell’s group Yoko Tajima used CRISPR gene editing to engineer mice carrying the human version of NOVA1.

Exhaustive analysis identified only subtle differences between the ‘humanized’ mice and normal rodents: when newborn mice were isolated from their mothers, pups with the human version of NOVA1 had altered distress calls. Similarly, in the presence of a female mouse in heat, male mice carrying the change made more complex courtship calls.

In the mouse brains, the human version of NOVA1 affected a molecular process, called alternative splicing, in which coding sequences of other individual genes are mixed and matched to create diverse proteins. Some of the ‘alternatively spliced’ genes have been implicated in vocal behaviour. The results were published¹ on 18 February in Nature Communications.