Geneticists have successfully spliced a human DNA sequence into mice, resulting in rodents with increased brain mass, an achievement that offers new clues to human evolution.
The team behind the breakthrough reports that the addition of human genes increased average brain size by 6.5%, boosting neuron production and expanding the brain’s outer layer. These unique genetic effects provide scientists with a deeper understanding of how the human brain evolved to feature much larger proportions than those of other primates.
The Human Brain Grows Larger
Since diverging with chimpanzees from our common ancestor, the human brain has tripled in size, becoming the largest among primates. Previous attempts to identify the mechanism behind this growth had not yielded a definitive explanation.
One promising lead from earlier research involves human accelerated regions (HARs)—small segments of DNA found in mammals that underwent dramatic transformation in a short evolutionary span after the human-chimpanzee split. However, exactly how HARs contribute to brain expansion has remained unclear.
Peering into the Genetic Code
To investigate how HARs affect brain growth, the team focused on a specific HAR known as HARE5. Discovered only a decade ago, this segment has been linked to increased expression of the Fzd8 gene, which plays a key role in neural cell production. Researchers analyzed the effects of HARE5 across three species: humans, mice, and chimpanzees.
The team isolated HARE5 from human DNA and used it to replace the corresponding segment in mouse DNA. As the mice matured, researchers observed that those with the human version of HARE5 developed brains 6.5% larger than those of normal mice. Radial glia—neural stem cells essential for generating neurons and other brain cells—were the most significantly affected. These cells divided and proliferated more rapidly in the modified mice compared to those using the native mouse HARE5 sequence.
In comparing HARE5 variations, the team identified four specific mutations that distinguish the human version from the chimpanzee version, each contributing to enhanced cell production.
Despite the increased brain matter, researchers have not yet determined whether the genetic modification improved the mice’s cognitive or memory functions.
Toward a Fuller Understanding
To deepen their investigation into human brain evolution, the researchers are now turning to organoids—miniature human brain models grown in lab dishes. These models allow for a closer look at how neural cell production responds to HARE5.
So far, results show that organoids containing chimpanzee HARE5 produced fewer and less developed radial glia than those with human HARE5. By observing these models in action, the researchers also identified a key signaling pathway that HARE5 appears to amplify—an effect that increases stem cell growth and contributes to the development of larger, more complex adult brains.
The team recommends that future studies build on the HARE5 findings by examining how this enhancer interacts with the roughly 3,000 other HARs in the human genome. After making progress in understanding one piece of the puzzle, the researchers see the next logical step as figuring out how all the components work together.
“There are many, many different mechanisms that are critical to making the human brain what it is,” said co-author Debra Silver.
“There are many, many different mechanisms that are critical to making the human brain what it is,” said co-author Debra Silver.
The paper “A Human-specific Enhancer Fine-tunes Radial Glia Potency and Corticogenesis” appeared on May 14, 2025 in Nature.
Ryan Whalen covers science and technology for The Debrief. He holds an MA in History and a Master of Library and Information Science with a certificate in Data Science. He can be contacted at ryan@thedebrief.org, and follow him on Twitter @mdntwvlf.