When Four Letters Changed Everything: The Genetic Switch That Grew Our Minds

The hidden DNA switch that made human intelligence possible may be one of the most astonishing stories in evolution. In this article, here the study shows how just only four tiny changes in a non-coding DNA region helped and supercharge our brain development, capabilities setting humans completely apart from other primates.

It’s difficult to think that something is so tiny could make such a huge difference. Imagine: just four small changes in a stretch of DNA that doesn’t even code for proteins-barely a blip in our massive genome. Yet, these subtle tweaks might help spark the dramatic jump in brain size and smarts that set us, Homo sapiens, apart from our primate relatives. Sometimes, evolution really is all about the little things. Scientists from Duke University have zoomed in on a powerful regulatory segment of the genome known as HARE5 a "Human Accelerated Region" (HAR) that doesn't code for proteins but acts as a master enhancer during early brain development.

While humans share nearly 99% of their DNA with chimpanzees, these last fractions are where evolution's greatest signatures are etched. HARE5 is one of 3,000 HARs segments that changed rapidly after our split from chimpanzees. In this study, the researchers show that HARE5 exerts its influence near the Frizzled8 (FZD8) gene, a key player in the WNT signaling pathway , a molecular cascade crucial for guiding how neural stem cells proliferate and mature during early brain growth.

Small Sequence, Huge Consequence

What makes this study extraordinary is its precision. By isolating four human-specific nucleotide changes within HARE5, researchers demonstrated their powerful effect on brain development. These four substitutions, though minor in appearance, turbocharge HARE5's enhancer activity—especially during the window when neural progenitors multiply.

So, when researchers put the human version of HARE5 into mice, the results were honestly kind of very different, a kind of wild. The embryos ended up with bigger, more folded neocortices, and those radial glial cells-the ones that make neurons-were just, like, multiplying way faster than usual. Plus, these mice had more WNT signaling going on, which basically means HARE5 was making FZD8 get expressed more right when the brain’s doing all its important growing stuff.

Chimp vs. Human: A Tale of Cellular Timing

To further test these four mutations, researchers performed elegant gene-editing experiments on both human and chimpanzee stem cells. When the human HARE5 variant was placed into chimpanzee cells, neural progenitor proliferation significantly increased. In contrast, swapping in the chimpanzee version into human cells dampened that proliferation.

This suggests that even subtle edits in enhancer DNA—especially in early embryonic stages—can steer the course of neural architecture. The expansion of the neocortex, a layer responsible for reasoning, language, and memory, likely benefited from these minute molecular changes.

Brain images of 4 primate and 2 rodent species. Size ratios (yellow text) are based on brain weight. The scale bar applies to all images. Primate and mouse brain images were adapted with permission from ref. 3. Capybara (a gyrencephalic rodent) image courtesy of Suzana Herculano-Houzel, Vanderbilt University, Nashville, TN.

ADVERTISEMENTS

ADVERTISEMENTS

Evolution’s Trade-off: Brilliance Comes with Burden

But evolution is rarely a gift without cost. By-the-way, the same human-specific HARE5 sequence overlaps with genetic regions linked to neurodevelopmental disorders, including autism spectrum disorder. In tweaking enhancer activity to maximize brain growth and cognitive capabilities, evolution may have increased susceptibility to certain disorders—a genetic tightrope walk between brilliance and fragility.

Senior author Dr. Debby Silver suggests that while these findings only address four base changes, they reveal a pattern: complex traits like human cognition often emerge from layered, subtle shifts in genetic regulation—not massive genomic overhauls.

More Than a Mutation: A Map to Our Minds

This research shows that what makes us human isn’t just in protein-coding genes, but in the precise timing and location of gene activation. HARE5, once a genomic mystery, now symbolizes the evolutionary finesse behind our brain’s growth.

For more on the original research, see the full paper here: Nature article

Reference

Liu, J., Mosti, F., Zhao, H. T., Lollis, D., Sotelo-Fonseca, J. E., Escobar-Tomlienovich, C. F., Musso, C. M., Mao, Y., Massri, A. J., Doll, H. M., Moss, N. D., Sousa, A. M. M., Wray, G. A., Schmidt, E. R. E., & Silver, D. L. (2025). A human-specific enhancer fine-tunes radial glia potency and corticogenesis. Nature, Published 14 May 2025. https://doi.org/10.1038/s41586-025-09002-1

The evolutionary history of apes and humans is largely incomplete.

Whereas the phylogenetic relationships among living species can be retrieved using genetic data, the position of most extinct species remains contentious. Surprisingly, complete-enough fossils that can be attributed to the gorilla and chimpanzee lineages remain to be discovered. Assuming different positions of available fossil apes (or ignoring them owing to uncertainty) markedly affects reconstructions of key ancestral nodes, such as that of the chimpanzee-human LCA.

Image Credit: https://www.science.org/doi/10.1126/science.abb4363

ADVERTISEMENTS

ADVERTISEMENTS

Drop Us a Line

We’d Love to Hear from You

RECENT POSTS