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Human DNA gives mice bigger brains

Injecting mouse embryos with a human DNA sequence leads to a marked increase in brain size -- and may provide insights into Alzheimer's.

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Mouse embryo injected with HARE5. Gene actvity is stained blue. Duke University/Silver Lab

The human genetic code is very similar to the genetic code of our closest living relative -- the chimpanzee -- sharing around 95 percent. Of all the differences, however, one is particularly interesting: the human brain is a lot bigger than the brain of a chimp. The brain of a chimp weighs, on average, 384 grams, whereas a human brain is more than triple that, at 1,352 grams.

Although it's not brain size alone that accounts for human intelligence, it certainly plays a pretty important role -- and now, researchers at Duke University have identified the DNA sequence that may be responsible for that particular evolutionary deviation.

How? By using mouse embryos.

The DNA sequence, called HARE5, is a gene activity regulator shown to markedly increase the size of a mouse embryo's brain when injected into the embryo. Compared to a mouse embryo injected with chimpanzee HARE5, the mouse embryo's brain grew 12 percent larger.

"I think we've 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."

HARE5 is what is known as an "enhancer", belonging to a group called "human-accelerated regulatory enhancers", including HARE1 through to HARE6. Enhancers are short pieces of DNA inside every genome that control the activity of genes.

To locate the DNA that might influence brain development, the team screened databases of genomic data from humans and chimps, looking for enhancers expressed primarily in the brain tissue early in development, but that also differed between the two species. Of the 106 candidates, the HARE group were near to genes believed to be involved in brain development.

HARE5 was the strongest candidate -- it's located chromosomally near Frizzled8, a molecular pathway indicated in brain development and disease. The team also found that Frizzled8 and HARE5 make physical contact in brain tissue.

Interestingly, human HARE5 and chimpanzee HARE5 are very similar. However, when introduced into mouse embryos, the differences were pronounced.

Mice with human HARE5 showed faster proliferation of neuron progenitor cells than mice with chimp HARE5 -- resulting in more neurons, and affecting the neocortex -- the region of the brain involved in higher functions, such as language and reasoning. Towards the end of gestation, the size difference in the brains was visible to the naked eye.

"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," Silver said.

The research, the team believes, could be useful in gaining insight into specific brain conditions, such as autism and Alzheimer's disease -- conditions that don't affect chimpanzees.

The full study can be found online in the journal Current Biology.