Scientists use human DNA to enlarge mice brain

Scientists have increased the size of mice brains by giving the rodents a piece of human DNA that controls gene activity.
Duke University scientists 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 per cent bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.
The findings, published in the journal 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 Alzheimer's disease, whereas chimpanzees don't.

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.
Researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritised enhancers that differed markedly between the two species.
The group's 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 Frizzled 8 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.

"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 Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke Medical School.
The researchers found that in the mouse embryos equipped with Frizzled 8 under control of human HARE5, progenitor cells destined to become neurons proliferated faster compared with the chimp HARE5 mice, ultimately leading to more neurons.
As the mouse embryos neared the end of gestation, their brain size differences became noticeable to the naked eye.

Graduate student Lomax Boyd started dissecting the brains and looking at them under a microscope.
Human HARE5 mice had brains 12 per cent larger in area compared with chimpanzee HARE5 mice. The neocortex, involved in higher-level function such as language and reasoning, was the region of the brain affected.