A unique piece of human DNA, when inserted into mice, caused the animals to grow brains about 6.5% larger than normal, according to a new study published in Nature.
The DNA segment, known as HARE5, acts like a genetic switch. It boosts the activity of genes that control brain development — specifically by increasing the number of cells that eventually become neurons. This could help explain how human brains became significantly larger than those of other primates.
This study gives a much clearer picture than previous ones
Katherine Pollard, a bioinformatics expert at the Gladstone Institutes in San Francisco.
Unlocking brain growth
Despite advances in neuroscience, how the human brain grew so large and complex over time is still a mystery. “We don’t yet have a complete answer for how our brains tripled in size after diverging from chimpanzees,” says Gabriel Santpere Baró, a genomics researcher in Barcelona, Spain.
Previous studies have suggested that Human Accelerated Regions (HARs) — fast-evolving stretches of DNA — may be involved. These regions are nearly identical across mammals but changed rapidly in humans. One of these, HARE5, was the focus of the new study led by Debra Silver, a developmental neurobiologist at Duke University.
Researchers replaced the mouse version of HARE5 with the human version. As the mice matured, their brains ended up significantly larger than those of regular mice. The key changes happened in radial glial cells — stem cells that give rise to neurons. With human HARE5, these glial cells divided more rapidly and produced more neurons.
We don’t yet know if the larger brains made the mice smarter
Silver
Small mutations, big effects
When comparing the human and chimp versions of HARE5, researchers found four specific mutations in the human version that significantly enhanced neural cell growth in both mouse and human models.
To investigate further, the team used miniature 3D brain organoids — tiny lab-grown versions of human brains. Organoids with the human version of HARE5 developed more mature and abundant radial glial cells compared to those with the chimp version. The human HARE5 also boosted a major signaling pathway that helps neural stem cells grow.
This supports the idea that HARE5 plays a key role in increasing brain size and complexity
Silver
What’s next?
Santpere Baró emphasizes the need to study how HARE5 interacts with the other 3,000+ HARs in the human genome. “These regions are a treasure trove for understanding human brain evolution,” he says.
Silver’s team is already exploring how different HARs might work together. “Many mechanisms contribute to what makes the human brain unique,” she says.
