A team of scientists at Duke University made a mouse just a bit more human.
They didn’t give it speech or opposable thumbs. They gave it something much smaller — a tiny stretch of human DNA known as HARE5. And in return, the mouse grew a brain about 6.5% bigger than its peers.
The tweak was minuscule. But the effect — a thickened outer cortex teeming with new neurons — could help explain one of the biggest mysteries in evolution: how our ancestors’ brains tripled in size after diverging from chimpanzees millions of years ago.
“We still do not have a definitive answer to how the human brain has tripled in size since our split from chimpanzees,” said Gabriel Santpere Baró, a neuroscientist at the Hospital del Mar Medical Research Institute in Spain. This study, apparently, gets us closer to understanding.
A Human Brain Accelerator
The study, published in Nature, dives into a small but powerful group of DNA sequences known as Human Accelerated Regions, or HARs. These segments are nearly identical in all mammals — except us. In humans, they’ve rapidly mutated since we branched off from our primate relatives.
Most HARs don’t code for proteins. Instead, they serve as enhancers — switches that dial nearby genes up or down. Scientists have long suspected that HARs are part of the recipe that makes human brains so big and intricate, but proving that has been difficult.
The team, led by developmental neurobiologist Debra Silver, focused on one particular enhancer: HARE5, which boosts a gene called Frizzled8, or Fzd8, known to play a role in early brain development.
Silver had identified HARE5 over a decade ago. But now, using an arsenal of tools — including genetically edited mice, chimpanzee and human brain organoids, and single-cell RNA sequencing — her team has mapped out in detail how this enhancer helps build a bigger brain.
“The story is much more complete and convincing,” said Katherine Pollard, a bioinformatician at the Gladstone Institutes who first coined the term HARs in 2006.
When the researchers replaced the mouse version of HARE5 with the human version, they watched the mice’s brains grow — not just in size, but in complexity. Under the microscope, the brains revealed more radial glia, a type of neural stem cell that multiplies early in development and gives rise to neurons.
These humanized mice produced more excitatory neurons and displayed greater functional independence between brain regions, suggesting not just more cells, but more refined circuitry.
Organoids and Origins
To test whether the findings held beyond mice, the team grew 3D miniature brain models — or organoids — from human and chimpanzee stem cells. When they inserted human HARE5 into chimpanzee cells, they observed the same pattern: increased radial glial proliferation and faster maturation.
Looking closer, the researchers pinpointed four mutations unique to the human HARE5. Each of these genetic changes — absent in chimpanzees — acted like a volume knob, turning up enhancer activity. Together, they dialed up the WNT signaling pathway, a cascade of molecular messages crucial for neural growth.
“These findings illustrate how small changes in regulatory DNA can directly affect critical signalling pathways to modulate brain development,” the authors wrote.
Still, it’s not yet clear whether those larger mouse brains make for smarter mice but tests are underway.
Building the Big Picture
HARE5 is just one of over 3,000 HARs scattered across the human genome. Each may contribute a small piece to the puzzle of human brain evolution. Together, they likely interact in complex ways — amplifying, dampening, or redirecting one another.
“They still represent a genetic treasure trove that we must keep digging into,” said Santpere Baró.
Silver’s lab is now developing new methods to study how these HARs function together. It’s possible that entire networks of enhancers, each subtly shaping the growth and wiring of the cortex, formed the genetic scaffolding that allowed humans to outsmart every other species.
In a sense, our brains may be the sum of tiny tweaks — not to the genes themselves, but to the instructions that control them.
It’s not evolution by brute force, but by fine-tuning.
“There are many, many different mechanisms that are critical to making the human brain what it is,” Silver said.
