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"We found a piece of the genetic basis for why we have a bigger brain," said Gregory Wray, professor of biology and director of the Duke Center for Genomic and Computational Biology.

The human version of a DNA sequence called HARE5 turns on a gene important for brain development (blue), causing a mouse embryo to grow a 12 percent larger brain by the end of pregnancy than an embryo injected with the chimpanzee version of HARE5. Image Credit: Silver lab, Duke University

Evolving a bigger brain with human DNA

Tiny but crucial DNA difference between human and chimp DNA boosts a larger brain size in mice given the same human gene.

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

Duke scientists now show how it's possible to pick out key changes in the genetic code of chimpanzees and humans in order to visualize their early brain development — through the study of mouse embryos.

The team found brain development is affected by tiny differences in one gene activity regulator called HARE5.

Introduced into a mouse embryo, human HARE5 led to a 12% bigger mouse brain than in mouse embryos treated with chimpanzee HARE5.

These findings, online in the Feb. 19, 2015 Current Biology, may not only tell us what makes the human brain unique, but also why we get diseases such as autism and Alzheimer's when chimpanzees do not.

"I think we've just scratched the surface, in terms of what we can gain from this sort of study," said Debra Silver, assistant professor of molecular genetics and microbiology at 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 only in certain tissues. But none of the human-specific enhancers had been known to influence brain anatomy specifically.

Researchers mined genomic databases for humans and chimpanzees to find DNA enhancers expressed primarily in the early brain. Prioritizing the finding of enhancers markedly different between the two species.

An initial screenning turned up 106 candidates, six near genes believed to be involved in brain development. They were named 'human accelerated regulatory enhancers' or HARE. Sequentially naming them HARE1 through to HARE6. The strongest candidate was HARE5.

HARE5 is located near a gene called Frizzled 8 which itself is part of a well-known molecular pathway implicated in brain development — and disease. The group decided to focus on HARE5 as it was likely to be an enhancer for Frizzled8 as the two DNA sequences are in physical contact within the brain.

Human HARE5 ('human-accelerated regulatory enhancer' gene sequencer) and the chimpanzee HARE5 differ by only 16 letters in their genetic code.

Yet, in mouse embryos researchers found that human HARE5 enhancer was active earlier in fetal development and more active in general than chimpanzee enhancer.

"What is really exciting is that the activity differences detected were at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," Silver added. Researchers found that in mouse embryos equipped with Frizzled8 and under the control of human HARE5, progenitor cells destined to become neurons proliferated faster than those in the chimp HARE5 mice.

Ultimately, the fast proliferation of progenitor cells led to more neurons in mouse embryos equipped with human HARE5.

As mouse embryos neared the end of gestation, brain size difference became noticeable to the naked eye. Graduate student Lomax Boyd dissected each brain under a microscope. Silver: "We took a ruler and measured. Although we were blind to what each mouse genotype was, we started noticing a trend."

All told, mice modified with human HARE5, had brains 12% larger in area than mice modified with chimpanzee HARE5. The neocortex, involved in higher-level function such as language and reasoning, was the brain region most affected.

Producing a short list of strong candidates was a feat in itself, said co-author Gregory Wray, professor of biology and director of the Duke Center for Genomic and Computational Biology. Wray: "Many others have tried this and failed. We've known other people who have looked at genes involved in brain size evolution, tested them out and done the same kinds of experiments we've done and come up dry."

The Duke team plans to study the human HARE5 and chimp HARE5 mice into adulthood, for possible differences in brain structure and behavior. The group also hopes to explore the roles of the remaining five HARE sequences and to what degree they affect brain development as well.

Abstract
Highlights
•Discovery of a human-accelerated enhancer functioning in the developing neocortex
•Compared to chimpanzee, human HARE5 drives earlier and more robust brain expression
•The HARE5 locus physically contacts the core promoter of the WNT receptor, Fzd8
•HARE5::Fzd8 mice have an accelerated neural progenitor cell cycle and enlarged brains

Summary
The human neocortex differs from that of other great apes in several notable regards, including altered cell cycle, prolonged corticogenesis, and increased size [ 1–5 ]. Although these evolutionary changes most likely contributed to the origin of distinctively human cognitive faculties, their genetic basis remains almost entirely unknown. Highly conserved non-coding regions showing rapid sequence changes along the human lineage are candidate loci for the development and evolution of uniquely human traits. Several studies have identified human-accelerated enhancers [ 6–14 ], but none have linked an expression difference to a specific organismal trait. Here we report the discovery of a human-accelerated regulatory enhancer (HARE5) of FZD8, a receptor of the Wnt pathway implicated in brain development and size [ 15, 16 ]. Using transgenic mice, we demonstrate dramatic differences in human and chimpanzee HARE5 activity, with human HARE5 driving early and robust expression at the onset of corticogenesis. Similar to HARE5 activity, FZD8 is expressed in neural progenitors of the developing neocortex [ 17–19 ]. Chromosome conformation capture assays reveal that HARE5 physically and specifically contacts the core Fzd8 promoter in the mouse embryonic neocortex. To assess the phenotypic consequences of HARE5 activity, we generated transgenic mice in which Fzd8 expression is under control of orthologous enhancers (Pt-HARE5::Fzd8 and Hs-HARE5::Fzd8). In comparison to Pt-HARE5::Fzd8, Hs-HARE5::Fzd8 mice showed marked acceleration of neural progenitor cell cycle and increased brain size. Changes in HARE5 function unique to humans thus alter the cell-cycle dynamics of a critical population of stem cells during corticogenesis and may underlie some distinctive anatomical features of the human brain.

The work was supported by a research incubator grant from the Duke Institute for Brain Sciences, the National Institutes of Health (R01NS083897), and National Science Foundation (HOMIND BCS-08-27552).

CITATION: "Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex," J. Lomax Boyd, Stephanie L. Skove, Jeremy Rouanet, Louis-Jan Pilaz, Tristan Bepler, Raluca Gordan, Gregory A. Wray, Debra L. Silver. Current Biology, February 19, 2015. DOI: 10.1016/j.cub.2015.01.041.

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