Specific Genetic Enhancers May Have Contributed to Larger Brains in Humans


Though humans don’t have the largest and most complex brains of the mammals (those distinctions go to the sperm whale and the elephant, respectively), the complexity of our language and our societies– as well as the fact that we are human and therefore innately obsessed with navel-gazing– has led us to question what makes our brains unique amongst our fellow animals.

A study published just a few days ago in Current Biology by Lomax Boyd et al. suggests that genetic enhancers, pieces of regulatory noncoding DNA that can reside up to 1 million base pairs away from their target genes, may have played an important role in brain growth, setting humans apart from our nearest living relative, the chimpanzee. Because DNA coils into compact packages, proteins bound to enhancer sequences can come into contact with transcription factors bound to gene promoters even though they may be many basepairs away from one another, allowing them to interact, stimulate, or even enhance gene expression.

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Diagram showing the basic concept of an enhancer sequence. The enhancer contains a binding site for an activator protein. When the DNA is shaped such that the protein bound to the enhancer sequence binds to other proteins bound to the promoter sequence (TATA box), gene expression is either induced or upregulated. Image borrowed from here.

The recent study out of Duke, however, has used mouse models to study the effects of a specific enhancer sequence on brain development known as HARE5, which enhances gene expression of FZD8, a well-known target of the growth-related Wnt pathway. Specifically, Lomax Boyd et al. designed two mouse models: in one model, they inserted the human version of the HARE5 sequence upstream of the mouse Fzd8 gene, meanwhile in the other they inserted the chimpanzee HARE5. Then they watched how the brains of the mice developed.


What they found was that the mice with the human HARE5 enhancer showed accelerated brain growth, as well as larger overall brain size, as compared to mice with the chimpanzee enhancer. While it’s impossible to say that the effects of HARE5 are the same or similar in their species of origin (human vs. chimp), it does suggest that the specific differences in sequence between the human and chimp enhancer sequences may have led to some pretty substantial differences in brain development between our two closely-related species.

HARE5 is just one enhancer sequence that may have played a role in human brain evolution, though there are undoubtedly other enhancers and regulatory sequences that have played their parts as well. In terms of brain evolution, it’s not just size that matters but complexity. And in order to create the kind of complexity seen in the human brain, that takes a lot of small changes in many different interactive players. As food for thought, consider that the above mouse models are probably lethal in the mouse, or at worst, lead to some extensive mousey-version intellectual disability. So for the human HARE5 to have been useful, it most likely had to occur on an evolutionary background that could accommodate such changes. Which is why evolution is 1 part genius and 9 parts sheer luck.

Further study of enhancer sequences, as well as their diametric counterparts, the silencers, may provide considerable insight in the study of human brain evolution. While even single point mutations in coding sequences can lead to disastrous outcomes, minor changes to regulatory sequences such as enhancers and silencers, which often function in tissue specific manners (e.g., kidney vs. brain), may alter the biological landscape just enough that extreme disability or lethality are avoided and minor adaptations are allowed to persist and spread through the gene pool. While we share extensive sequence homology of coding DNA with animals with whom we share a common ancestor from hundreds of millions of years ago, changes to the gene regulators instead make the greatest difference between a human, a chimpanzee, a mouse, a chicken, a turtle, and a fish.

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