This is your brain on Human accelerated regulatory enhancer (HARE5)

Pinky and the Brain

Four decades have passed since King and Wilson published their seminal paper “Evolution at Two Levels in Humans and Chimpanzees“. In it, they proposed that the large behavioral and morphological differences between us and our closest relatives, chimpanzees, could not be accounted for by the minimal molecular differences between us at the level of proteins; rather that these behavioral and morphological differences were more likely to be due to changes in mechanisms that regulate the expression of genes.
We’ve come a
long way since then.
We have now identified numerous regions that have rapidly diverged from chimps – appropriately called “human accelerated regions” (HARs) – regions that might help to explain the evolution of uniquely human traits (think language and enhanced cognitive abilities). Indeed, as King and Wilson proposed, many of these HARs include changes in regulatory regions (e.g., enhancers, which are typically identified by H3K4me1 modifications or, more recently/functionally, using STARR-seq). Yet despite these numerous advances, we still know little, if any, about the causal link between such regulatory changes and the corresponding organismal-level differences.
A new paper by J. Lomax Boyd and colleagues from Duke University connects some of these dots by linking genetic differences between humans in chimps to their corresponding differences in form – specifically brain size (and, potentially, differences in cognition). Lomax and colleagues scanned through a bunch of HARs and found one, HARE5, that was particularly promising. HARE5 is an enhancer that regulates the expression of FZD8 – a gene that is tied to brain development and size.
The human and chimp versions of HARE5 differed by only 16 base pairs, but these 16 little changes had a whopping effect. First, they used chromosome confirmation capture assays to confirm that HARE5 physically contact the FZD8 promoter in the (mouse) neocortex – strong confirmation of its regulatory role and connection. Second, when they put the human version of HARE5 into transgenic mice, they found that it led to a 12% increase in brain size compared to the transgenic mice with the chimp version of HARE5:
Transgenic mouse embryos reveal that the human version (Hs, right) of HARE5 leads to earlier and larger development (as shown by more widespread and darker blue) of the brain than the chimp version.

Transgenic mouse embryos reveal that the human version (Hs, right) of HARE5 leads to earlier and larger development of the brain than the chimp version. From Boyd et al., 2014

So what does this all mean?
In a recent email, Dr. Boyd told me that:

“Our work provides one of the few studies that tests the functional consequences of rapidly evolving ​regions of the human genome on a developmental process, providing both a link to an overlaying phenotype and a molecular mechanism. We also provide some of the strongest evidence for a molecular/developmental pathway that may be directly involved in regulating the evolution of human brain size.”

So what’s next?

“As an evolutionary biologist, we ultimately care about the trait under selection, which for the brain is behavior. What are the behavioral consequences of these human-specific mutations?”, said Dr. Boyd.

In other words, do these bigger brains lead to better cognitive abilities? Might they explain some of the large differences between human and chimp cognitive abilities? For these and other answers we’ll have to wait for the results of future cognitive tests (probably mazes!) on the human HARE5 transgenic mice.
King MC & Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188, 107–116.
Boyd JL, Skove SL, Rouanet JP, Pilaz L-J, Bepler T, Gordân R, Wray GA & Silver DL (2015) Human-Chimpanzee Differences in a FZD8 Enhancer Alter Cell-Cycle Dynamics in the Developing Neocortex. Curr. Biol.

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