Five people, one mutation and the evolution of human language

The Sylvian fissure (via BodyParts3D/Wikimedia Commons)
The Sylvian fissure (via BodyParts3D/Wikimedia Commons)
Five people with an unusual pattern of brain folds have afforded a glimpse into how the human brain may have evolved its language capabilities.

How the human brain develops its hills and valleys—expanding its surface area and computational capacity—has been difficult to study. Mice, the staple of scientific research, lack folds in their brains.

Christopher Walsh, MD, PhD, head of the Division of Genetics and Genomics at Boston Children’s Hospital, runs a brain development and genetics clinic and has spent 25 years studying people in whom the brain formation process goes awry. Some brains are too small (microcephaly). Some have folds, or gyri, that are too broad and thick (pachygyria). Some are smooth, lacking folds altogether (lissencephaly). And some have an abnormally large number of small, thin folds—known as polymicrogyria.

In 2005, studying people with polymicrogyria, Walsh and colleagues identified a mutation in a gene known as GPR56, a clue that this gene helps drive the formation of folds in the cortex of the human brain.

In a study published in today’s issue of Science, Walsh and his colleagues focused on five people whose brain MRIs showed polymicrogyria, but just in one location—near a large, deep furrow known as the Sylvian fissure, which includes the brain’s primary language area.

“This gave us a chance to study very localized cortical patterning,” says Byoung-Il Bae, PhD, co-first author of the paper.

The five people studied—three Irish Americans and two from Turkey—had impairments in cognition and language, as well as seizures. None had mutations in GPR56, nor was anything amiss in any of their other genes. But in addition to genes, our DNA includes many “non-coding” regions that are believed to regulate gene function and are only beginning to be understood. Bae and his co-first author Ian Tietjen, PhD, took the lead in searching about 40 of these non-coding regions, and in one, they struck gold.

Each of the five patients had a tiny deletion in their DNA sequence—just 15 base pairs or “letters” of genetic code—in precisely the same location: right next to the GPR56 gene.

A brain divergence

Genetically, the finding is somewhat of a landmark. “There are only two or three other examples of mutations that occur outside the gene,” says Walsh.

And here’s where the evolutionary intrigue comes in. Some 85 to 100 million years ago, placental mammals branched off from marsupials and egg-laying mammals. Around this time, an odd event took place: The placental mammals, the family we belong to, acquired some additional DNA—possibly through a virus-like bit of genetic code known as a retrotransposon inserting itself into the genome.

Some of this new DNA is precisely where the five individuals’ mutations lie. The inserted genetic code functions as a promoter—the “start” site for transcribing the GPR56 gene so that it can function. Studying human tissue and genetically modified mice, Walsh, Bae and colleagues found that increased transcription of GPR56, driven by this promoter region, caused a surge of neural stem cells specifically in the area of the Sylvian fissure, while loss of GPR56 decreased neural stem cell production, thinning the cortex in that area.

Because it drives growth around the Sylvian fissure—and perhaps even helps account for the fold’s existence—Walsh and Bae believe this promoter region may have helped set the stage for humans to develop language. “Most evolution is believed to involve change in the non-coding part of the genome,” says Walsh. “It’s a way of adapting a gene so its expression is regulated in a very specific way.”

While all placental mammals have this promoter region, humans have taken genetic innovation even further, the researchers found. Mice, whose brains lack convolutions, have just five transcription start sites in the area around GPR56. Humans have a total of 17.

“We think this promoter region was evolutionarily expanded in humans,” says Bae. “Expansion of promoters may be a very good way to fine-tune regional cortical patterning. It’s quite useful to be able to fine-tune GPR56 expression, rather than play with one or just a small number of these ‘switches.’”

That fine-tuning—which remains to be explored in more depth—could be what makes human language so rich and complex. If you’ve read this far and I’ve told this story clearly, you might have some of these 17 promoters to thank.