Scientists have long struggled to explain what sets the human brain apart. Our cerebral cortex, the folded outer layer dedicated to thought, speech, and imagination is three times as large as the cerebral cortex of our nearest relatives, the chimpanzees. Now research shows a microscopic shift in our DNA embedded inside a regulatory on-off switch known as HARE5 might be the key to this evolutionary jump.
By examining this microscopic genetic enhancer, scientists have discovered how a few mutations unique to humans accelerated brain development, resulting in the rapid proliferation of neurons that characterize our species. In addition to rewriting our knowledge of human evolution, the discovery creates new avenues for the treatment of neurodevelopmental disorders.
The Genetic “Dark Matter” That Shaped Human Intelligence
Some DNA functions as a conductor, coordinating the location and timing of gene activation, while other DNA does not build proteins. Human Accelerated Regions (HARs) are regulatory sequences that were almost unaltered for millions of years prior to the evolution of humans. HARE5, an enhancer near the Frizzled gene (a critical player in brain development), carries four human-specific mutations.
When scientists inserted the human version of HARE5 into mice, something astonishing happened: their brains grew larger, packed with more neurons. This suggests that a few subtle tweaks in our DNA didn’t just alter brain size, they supercharged the very process of building a mind.
Mice With Human Brains: A Radical Experiment
In order to test HARE5’s potency, researchers used CRISPR gene-editing to give mice the human version. The results were stunning:
- 12% bigger neocortex (the part of the brain responsible for higher thinking)
- Higher neuron growth, in this instance, excitatory neurons that enable advanced thinking
- Greater functional autonomy between brain regions, reflective of higher-level cognition
These mice did not start writing poetry right away, but their brain structure mimicked significant features of human brain development to warrant HARE5’s position in our family tree.
The Secret of the “Brain-Boosting” Enhancer
How does HARE5 work? The answer lies in radial glial cells, the brain’s neural stem cells during early development. They divide in two modes:
- Self-renewal: Replicating themselves to enable the “factory” to keep running.
- Neurogenesis : Creating neurons that make up the brain’s wiring.
Human HARE5 prolongs the phase of self-renewal to enable radial glia to accumulate more neural building blocks before changing to neuron production. The delay creates a greater reservoir of progenitors, resulting in a neuron explosion just what occurred in human evolution.
WNT Signaling: The Brain’s Growth Accelerator
HARE5 doesn’t act alone. It cranks up canonical WNT signaling, a pathway that tells cells when to multiply. In human neural stem cells, the enhancer’s mutations amplify this signal, creating a feedback loop that keeps radial glia dividing longer.
When scientists tested chimpanzees and human brain organoids side-by-side, the human cells proliferate faster but only when HARE5 was active. Blocking WNT signaling erased this advantage, confirming the pathway’s crucial role.
Why Didn’t Other Primates Get This Upgrade?
If HARE5 is so powerful, why don’t chimps have it? The answer lies in evolution’s tinkering:
- The chimp version of HARE5 is weaker, producing fewer neural progenitors.
- Human mutations fine-tuned the enhancer’s activity, making it more responsive at key developmental stages.
- Timing was everything slight delays in neurogenesis allowed for more growth.
This suggests that small regulatory changes, not just new genes, drove our cognitive revolution.
Beyond Evolution: Could HARE5 Help Treat Brain Disorders?
Understanding HARE5’s role isn’t just about the past it could shape the future of medicine. Disorders like microcephaly (abnormally small brains) and autism (altered neural connectivity) may stem from glitches in similar regulatory networks.
By mapping how enhancers like HARE5 control brain development, scientists may be able to ultimately repair defective development or even create smarter neural organoids for drug testing.
The Bigger Picture: A New Era of Evolutionary Neuroscience
This discovery reshapes how we see human uniqueness. It wasn’t just a single “intelligence gene” that made us smarter, it was precision tweaks to ancient regulatory code. HARE5 is likely just one of many such switches waiting to be uncovered.
As geneticists dig deeper into HARs, we may finally decode the full instruction manual behind the human brain revealing how a handful of molecular changes birthed art, science, and the very act of wondering how we came to be.
Final Thought
If a few DNA letters could make our brains triple in size, what other evolutionary secrets are hiding in our genome? The search has only just begun.
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Jan loves Wildlife and Animals and is one of the founders of Animals Around The Globe. He holds an MSc in Finance & Economics and is a passionate PADI Open Water Diver. His favorite animals are Mountain Gorillas, Tigers, and Great White Sharks. He lived in South Africa, Germany, the USA, Ireland, Italy, China, and Australia. Before AATG, Jan worked for Google, Axel Springer, BMW and others.