Evolving a Bigger Brain With Human DNA

Durham, NC - The size of the human brain expanded dramatically during the course of evolution, imparting us with unique capabilities to use abstract language and do complex math. But how did the human brain get larger than that of our closest living relative, the chimpanzee, if almost all of our genes are the same?

Duke scientists have shown that its possible to pick out key changes in the genetic code between chimpanzees and humans and then visualize their respective contributions to early brain development by using mouse embryos.

The team found that humans are equipped with tiny differences in a particular regulator of gene activity, dubbed HARE5, that when introduced into a mouse embryo, led to a 12% bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.

The findings, appearing online Feb. 19, 2015, in Current Biology, may lend insight into not only what makes the human brain special but also why people get some diseases, such as autism and Alzheimers disease, whereas chimpanzees dont. I think weve just scratched the surface, in terms of what we can gain from this sort of study, said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School. 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.

Every genome contains many thousands of short bits of DNA called enhancers, whose role is to control the activity of genes. Some of these are unique to humans. Some are active in specific tissues. But none of the human-specific enhancers previously had been shown to influence brain anatomy directly.

In the new study, researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritized enhancers that differed markedly between the two species.

The groups initial screen turned up 106 candidates, six of them near genes that are believed to be involved in brain development. The group named these human-accelerated regulatory enhancers, HARE1 through HARE6.

The strongest candidate was HARE5 for its chromosomal location near a gene called Frizzled 8, which is part of a well-known molecular pathway implicated in brain development and disease. The group decided to focus on HARE5 and then showed that it was likely to be an enhancer for Frizzled8 because the two DNA sequences made physical contact in brain tissue.

The human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters in their genetic code. Yet, in mouse embryos the researchers found that the human enhancer was active earlier in development and more active in general than the chimpanzee enhancer.

Whats 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, Silver said.

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Evolving a Bigger Brain With Human DNA