Researchers have tied a particular gene to the development of cortical convolutions -- the prominent but enigmatic folds covering the surface of the human brain. Their discovery should shed some light on these characteristic contours, which have been the subject of wild speculation for ages, and perhaps also provide a better understanding of how such brain ridges form, how they evolved from our pre-human ancestors and, ultimately, how they influence brain function.

The exact role of cortical convolutions remains unknown, but theories have abounded. (Some, for example, have suggested that the folds act as the body's cooling system and others have even proposed that Albert Einstein's genius could have been traced to a single cortical fold on his brain.)

Now, leveraging advances that permit a closer look at how these folds develop, research published in the 14 February issue of Science shows that a mutation affecting GPR56 causes cortical convolutions around the brain's Sylvian fissure -- a particularly deep indentation -- to develop thinner and more convoluted than usual. The finding, which suggests that genes may assert control over the brain's physical folding on a section-by-section basis, provides insight into the mysterious cortical development process.

"There is already a list of genetic mutations that cause abnormal neocortical folding, which can be used for prenatal testing," explained Byoung-il Bae from the Division of Genetics and Genomics at Boston Children's Hospital and Harvard Medical School in Boston, Massachusetts, one of the lead authors of the Science report. "We intend to add this mutation to some of the panels."

Bae and colleagues from around the world investigated the genomes of five individuals with abnormalities on Broca's area, or the language center of the brain. These study participants were from three different families -- one Turkish and two Irish-American -- and they suffered from refractory seizures as well as intellectual and language difficulties.

The researchers found that all five patients harbored a mutation on a particular regulatory element that influences the GPR56 gene. Such regulatory DNA doesn't code for any proteins itself but promotes the expression of genes elsewhere on the genome. Geneticists have long-suspected that such non-coding regions of the genome could play important roles in evolution. To observe the specific effects of the GPR56 "promoter" DNA sequence, Bae and his team used genetically modified mice.

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They discovered that low expression of GPR56 (gauged by low levels of mRNA) decreases the production of neuroprogenitor cells -- those that will eventually give rise to neurons -- around Broca's area and the Sylvian fissure. By contrast, overexpression of the gene boosts the production of such progenitor cells in that region. The mutated piece of promoter DNA documented by the researchers, however, isn't the only non-coding segment on the genome that affects GPR56, they say.

This particular GPR56 promoter is found only in the genomes of placental mammals -- not egg-laying mammals, marsupials or non-mammals -- so Bae et al. suggest that it emerged after the lines of placental and non-placental mammals split, approximately 85 to 100 million years ago.

"Our story tells us that the regional proliferation of progenitor cells is controlled by multiple promoters that enable the formation of distinct gyri (folds) in different parts of the brain," said Bae. "Such promoters introduce more switches for the same proteins, and they may have been among the genetic tools our pre-human ancestors relied upon to evolve."

The human GPR56 gene has much more complicated promoters and regulatory elements than the mouse gene, which may suggest more refined control over brain development in humans, according to the researchers. To illustrate their point, Bae compared the mouse GPR56 promoters to a car's dashboard and the human GPR56 promoters to an airplane's dashboard: "The airplane dash has many more switches, and therefore pilots have more control -- sometimes over things that car drivers cannot even imagine."

"By regulating populations of progenitor cells in different parts of the brain with such promoter elements, our pre-human ancestors may have controlled the regions that grew over evolutionary time," he said.

But what purpose do cortical convolutions actually serve? Bae imagines them to represent a developmental strategy for packing enormous numbers of neurons and glial cells into the limited space of the skull. "Humans have 12 times the amount of neurons that chimpanzees have," he explained. "But the volume of our skull is only three times bigger."

Regardless of their precise role, however, the identification of this novel regulatory element affecting GPR56 will complement the massive amount of RNA data that have been accumulating online.

"We need to compile all of the available data at one convenient place… and make them easily accessible to scientists," Bae said. "If the huge amount of the RNA sequencing data is hoarded in a web server in a format that only bioinformaticians can dig into, then the efforts of this massive RNA sequencing are wasted."

The report by Bae et al. was supported by the Strategic Research Program for Brain Sciences and the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Funding Program for World-Leading Innovative R&D on Science and Technology; grant U01MH081896 from NIMH; grant 2R01NS035129 from NINDS; and The Paul G. Allen Family Foundation.