Editors' ChoiceNEUROGENETICS

Boosting our brains

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ec38
DOI: 10.1126/scitranslmed.aaa9498

The advanced cognitive capacity of humans is largely attributed to increased size and function of the brain. In particular, the size and cell density of the human neocortex is greater than that of chimpanzees—our closest great ape relative. Whereas humans share at least 95% of their genetic sequence with chimpanzees, there remains limited understanding of the genetic differences that drive unique human traits. Boyd et al. now show that the human-specific sequence of an FZD8 gene enhancer element functions to promote increased cortical size.

Since the sequencing of the human and chimpanzee genomes, there has been substantial interest in identifying functional sequence differences. Previous analyses have shown that genomic regions outside of those that encode genes have evolved at a rapid rate. These genomic loci have been termed human-accelerated regulatory enhancers (HARE), but researchers did not know whether HAREs functionally contributed to human-specific traits. In the new work, the authors directly tested the function of the human and chimpanzee HARE5—a 1219 base-pair enhancer located ~307 kilobases upstream of the FZD8 gene, which encodes a Wnt signaling-pathway receptor. The authors inserted into transgenic mice the human and chimpanzee HARE sequences, which differ at only 16 of the 1219 bases. Compared with chimpanzee, the human sequence significantly enhanced FZD8 gene expression 10- to 30-fold in the developing mouse cortex. Further, the human HARE5 sequence induced functional changes in cortical development, including acceleration of the cell cycle of neural progenitor cells. These effects resulted in enlargement of the mouse cortex by 12%, with a 14% increase in the number of FoxP1-positive cortical neurons.

This study suggests that the rapid evolution of enhancer elements is a key functional driver of the genetic basis of human-specific traits. Although there are potential caveats with the transgenic expression approach used by the authors, advancements in precise genome editing can be exploited to overcome these technical limitations. It will be illuminating to learn whether the human HARE5-specific enhancements of cortical size and density lead to cognitive or behavioral changes in the transgenic animals. A smarter mouse, perhaps?

J. L. Boyd et al., Human-chimpanzee differences in a FZD8 enhancer alter cell-cycle dynamics in the developing neocortex. Curr. Biol. 10.1016/j.cub.2015.01.041 (2015).[Abstract]

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