The Tiny DNA Switch That Helped Shape the Human Mind

What makes the human brain so different from that of our closest relatives? The answer is not found in a single gene but in stretches of DNA that regulate when and how other genes turn on. A new study from the University of California San Diego identifies one such region, a molecular “switch” called HAR123, that may have tilted our evolutionary trajectory toward greater flexibility of thought.

The findings, published in Science Advances¹, suggest that HAR123 influenced how our developing brains balanced the production of neurons and glial cells, two fundamental building blocks of neural circuits. That balance, in turn, may have opened the door to cognitive adaptability, the capacity to revise old information and learn new rules—a trait that sets humans apart from other primates.

“HAR123 is not a gene in itself, but a powerful enhancer that shapes the activity of other genes during brain development,” said senior author Miles Wilkinson, UC San Diego School of Medicine.

A Region That Evolved in the Fast Lane

HAR123 belongs to a class of DNA sequences known as human-accelerated regions (HARs). These are parts of the genome that remained largely unchanged across millions of years of mammalian evolution, only to undergo a burst of rapid mutations after the lineage leading to humans split from that of chimpanzees roughly 5 to 6 million years ago.

That burst of change suggests selective pressures were at play. Instead of drifting randomly, HARs likely carried alterations that offered advantages in cognition, development, or adaptation. In the case of HAR123, the research team found that its human-specific sequence drove stronger activity than the chimpanzee version when tested in neural progenitor cells.

Species-biased effects of HAR123 on human NPC generation. (A) scRNA-seq analysis of hESCs differentiated to the rosette stage of NPC generation. hESCs of four genotypes [described in (C)] were assayed independently and analyzed as a group to define the clusters shown in the uniform manifold approximation and projection (UMAP) plot. NPC-1 to -4 are four distinct NPC cell clusters, while the Diff. (differentiating) progenitor cluster has more developmentally advanced cells, based on markers shown in (B) and pseudotime analysis in (E). (B) Expression of the gene markers used for annotating the cell types in (A). exp, expression. (C) UMAP plots of the same scRNA-seq data as in (A), showing the cell contributions from the four indicated genotypes. (D) Quantification and pairwise comparison of the data in (C). Statistical analysis was done using one-way analysis of variance (ANOVA), followed by a Tukey post hoc test. Genotypes with different characters from a given cell cluster (a, b, c, or d) are significantly different in frequency from each other. P < 0.05. (E) Pseudotime trajectory analysis of the cells in (A). The arrow shows the direction of differentiation. (F) Left: Immunofluorescence analysis of differentiating neurons and glial cells from human NPCs of the indicated genotypes (two independent clones of each). NPCs were cultured under differentiation conditions (no fibroblast growth factor 2) for 4 weeks, following a standard neural differentiation protocol (20). Tubulin beta 3 class III (TUBB3) and glial fibrillary acidic protein (GFAP) mark neurons and glial cells, respectively. The cells were also stained with 4′,6-diamidino-2-phenylindole (DAPI; blue) to mark nuclei. Scale bar, 50 μm. Two biological replicates were performed. Right: Quantification of neuron/glia ratio of the indicated genotypes. Different letters (a, b, and c) denote statistically significantly different groups (P < 0.05).

These progenitor cells are the stem-like precursors that generate both neurons, responsible for processing information, and glia, which support and regulate neural networks. By tweaking how many of each type are produced, HAR123 may have fine-tuned the architecture of the human brain.

Cognitive Flexibility and the Human Condition

The study suggests HAR123 promoted an especially human trait: cognitive flexibility. This is the ability to discard outdated knowledge, adopt new strategies, and switch between modes of thinking. Archaeological records, from the appearance of new stone tool traditions to shifts in symbolic expression, reflect the importance of this trait throughout human prehistory.

“Our data suggest HAR123 may have contributed to the neural substrate that makes cognitive flexibility possible,” said co-author Kun Tan.

When the human and chimpanzee versions of HAR123 were compared in lab-grown stem cells, the enhancer shaped gene activity differently in each case. The human version promoted more dynamic regulation of neural progenitors, potentially granting our brains a broader repertoire of cell types and connections.

From Evolution to Disorder

The same molecular pathways that fueled the rise of human cognition may also underlie certain vulnerabilities. The authors note that HAR123, and HARs more broadly, are linked to neurodevelopmental conditions such as autism. While HAR123’s human-specific changes may have facilitated adaptability, they may also have introduced susceptibilities that our species continues to live with today.

Why This Matters for Human Origins

For anthropologists and archaeologists, HAR123 provides a molecular foothold for one of the most elusive questions in human evolution: how small tweaks in DNA rewired the brain. Unlike fossils or artifacts, enhancers such as HAR123 do not leave visible traces in the ground. Yet they may explain why our ancestors were capable of innovation, from Acheulean handaxes to Upper Paleolithic cave art.

In this sense, HAR123 bridges the molecular and the cultural, linking mutations in a regulatory sequence to the behaviors that define our lineage.

Related Research

1. Pollard, K. S., et al. (2006). “An RNA gene expressed during cortical development evolved rapidly in humans.” Nature, 443(7108), 167–172. https://doi.org/10.1038/nature05113

2. Hubisz, M. J., & Pollard, K. S. (2014). “Exploring the genesis and functions of Human Accelerated Regions sheds light on their role in human evolution.” Current Opinion in Genetics & Development, 29, 15–21. https://doi.org/10.1016/j.gde.2014.07.005

3. Doan, R. N., et al. (2016). “Mutations in human accelerated regions disrupt cognition and social behavior.” Cell, 167(2), 341–354.e12. https://doi.org/10.1016/j.cell.2016.08.071

4. Capra, J. A., et al. (2013). “Many human accelerated regions are developmental enhancers.” Philosophical Transactions of the Royal Society B, 368(1632), 20130025. https://doi.org/10.1098/rstb.2013.0025

1. Tan, K., Higgins, K., Liu, Q., & Wilkinson, M. F. (2025). An ancient enhancer rapidly evolving in the human lineage promotes neural development and cognitive flexibility. Science Advances, 11(33), eadt0534. https://doi.org/10.1126/sciadv.adt0534