At some point, over the course of evolution, the human brain expanded dramatically. This gave us the ability to build more and more complex tools, to learn mathematics and science and to develop complex, abstract languages. Our closes living relatives, the chimpanzees, weren’t so lucky,

Given that the genetic difference between us and the chimps is small, about 1 percent, what caused us to advance so much while the chimps were held back? A group of researchers at Duke University decided to try and track down the key differences.

The researchers picked out key genetic differences and then tracked the changes to brain development using mouse embryos. They found that small differences in a regulator of gene activity, which they labeled HARE5, led to a 12 percent larger brain when the human sequences was introduced over the chimpanzee sequence.

The researchers believe that it could provide an important clue as to what makes the human brain unique. It could also provide insight into conditions such as Alzheimer’s disease and autism which are not uncommon in humans but which do not appear to exist at all in chimps.

“I think we’ve just scratched the surface, in terms of what we can gain from this sort of study. There are some other really compelling candidates that we found that may also lead us to a better understanding of the uniqueness of the human brain,” said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School in a statement.

Every genome contains ‘enhancers’, small bits of DNA which control the activity of genes. Some of the enhancers present in the human genome appear to be unique and some are specific to certain tissues. However, to date, none have been found to influence the anatomy of the brain directly.

For their research, which appears online in Current Biology, the team mined genomic databases from humans and chimps to find enhancers expressed in the brain tissue early in development. They gave priority to enhancers which showed stark differences between the two species.

From an initial 106 candidates, the researchers narrowed the list to six that are believed to involve brain development. These “human-accelerated regulatory enhancers” were labeled HARE1 through HARE6.

It was decided that HARE5 was the best candidate because of its location near a gene called Frizzled 8. That gene is a known molecular pathway involved in both brain development and disease. The team was also able to show that the two DNA sequences make physical contact in brain sequences.

There are only 16 letters difference between the genetic code of the human HARE5 and the chimpanzee HARE5 sequences. However, in mouse embryos the researchers found that human HARE5 was active earlier in development and more active in general than chimpanzee HARE5.

“What’s really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons,” said Silver.

Near the end of gestation, the brain size of the sets of mouse embryos was visible to the naked eye.

“After he started taking pictures, we took a ruler to the monitor. Although we were blind to what the genotype was, we started noticing a trend,” said Silver.

In the end, the mice treated with human HARE5 had brains 12 percent larger compared with the chimpanzee HARE5 mice. Additionally, the region affected was the neocortex which is involved in higher-level functioning including language and reasoning.

The team now hopes to continue studying the mice into adulthood in order to better understand the HARE sequences in brain development.