Scientists Trace Human Brain Evolution To A ‘Tiny’ 442-Letter DNA Code

SAN DIEGO — A tiny stretch of DNA that’s been quietly evolving in humans for millions of years might hold the key to understanding what makes our brains different from our closest animal relatives. New research reveals that this genetic sequence, which rapidly changed after humans split from chimpanzees, plays a crucial role in brain development and could help explain uniquely human traits like advanced problem-solving and cognitive flexibility.

The discovery centers on a 442-letter genetic sequence called HAR123, buried deep within a gene that most people have never heard of. While this DNA snippet is present in mammals and marsupials, but absent in monotremes like the platypus, it has undergone dramatic changes in the human lineage since the human–chimpanzee split. Scientists at the University of California San Diego found that this rapidly evolving sequence acts like a genetic switch, controlling the development of brain cells in ways that differ subtly between humans and other species.

When researchers knocked out this sequence in laboratory mice, the animals developed problems with cognitive flexibility, struggling to adapt when familiar situations suddenly changed. In essence, they became less able to adjust their thinking when their environment shifted.

Ancient DNA Switch Controls Human Brain Development

HAR123 belongs to a special class of genetic sequences called Human Accelerated Regions (HARs), stretches of DNA that remained virtually unchanged for millions of years across different species, then suddenly started evolving rapidly in the human lineage. Scientists have identified about 3,000 of these sequences, and many of them act as genetic switches that control when and where other genes get turned on or off. HAR123 fits this pattern perfectly, functioning as what scientists call a “transcriptional enhancer,” essentially a genetic dimmer switch that can turn up or down the activity of nearby genes.

The research team, led by Dr. Kun Tan and Dr. Miles Wilkinson, discovered that HAR123 influences a gene called HIC1, which is involved in the generation of neural progenitor cells. When HAR123 activates HIC1, it helps ensure that developing brain cells mature into neurons rather than getting stuck in an immature state.

HAR123 actively promotes the formation of neural progenitor cells, the crucial building blocks that eventually become neurons and other brain cells. The hippocampus is a brain region critical for learning and memory, and the balance between neurons and support cells in this area appears to be essential for healthy brain function.

Lab Tests Show Cognitive Differences in Modified Mice

To understand what HAR123 actually does, the researchers conducted a series of experiments. They started with human embryonic stem cells and guided them through the process of becoming brain cells. When they removed HAR123 from these cells using precise genetic editing tools, the cells struggled to develop into proper neural progenitor cells.

The team then created mice with the HAR123 sequence completely removed. These knockout mice appeared normal on the surface. They could run, eat, and reproduce just fine. However, when scientists put them through cognitive tests, a specific problem emerged.

In one test, mice learned to find a hidden escape platform in a water maze by using visual cues around the room. Both normal mice and HAR123-knockout mice mastered this task equally well. But when researchers moved the platform to a different location, the knockout mice struggled to adapt. They kept searching in the old location, unable to flexibly adjust their strategy when the rules changed.

This type of cognitive inflexibility might seem minor, but it represents a fundamental difference in how the brain processes information and adapts to changing circumstances. In humans, cognitive flexibility allows people to switch between different concepts, adapt to new rules, and solve problems creatively.

Human vs Chimpanzee Brain Development Shows Key Differences

Perhaps most intriguingly, the researchers discovered that the human version of HAR123 behaves differently from the chimpanzee version. When they replaced the human sequence with its chimpanzee counterpart in human brain cells, the cells developed differently. The human version was better at promoting the formation of certain types of neural progenitor cells and influenced the balance between neurons and support cells in ways that the chimpanzee version did not.

HAR123 appears to have evolved specifically in humans to fine-tune brain development in subtle but important ways. The sequence favors the production of neurons over glial support cells, potentially contributing to the dense neural networks that characterize human brains.

The researchers also found that HAR123 controls the activity of many genes involved in nervous system development, and many of these genes are regulated differently by the human version compared to the chimpanzee version. This cascade effect means that small changes in HAR123 could have far-reaching consequences for how the brain develops and functions.

Brain Disorders and Human Evolution Connections

Beyond its role in normal brain development, HAR123 appears to influence the balance between different types of brain cells. When the researchers examined the brains of HAR123-knockout mice, they found altered ratios of neurons to glial cells in specific regions of the hippocampus. This imbalance persisted from early development into adulthood.

Many neurological and psychiatric conditions, including autism, schizophrenia, and Alzheimer’s disease, involve disrupted balances between different types of brain cells. HAR123 is located in a chromosomal region associated with rare neurodevelopmental disorders, making this connection even more compelling.

Scientists have long known that human brains are dramatically larger and more advanced than those of other primates, but the genetic changes responsible for these differences have remained largely mysterious. HAR123 provides a concrete example of how small genetic tweaks accumulated over millions of years might have contributed to uniquely human cognitive abilities.

Disclaimer: This research is an early-stage study conducted in laboratory models (stem cells and mice). While the findings suggest HAR123 may have contributed to human brain evolution and cognitive abilities, the direct impact on humans remains uncertain. Results should not be interpreted as proving how human intelligence evolved, but rather as offering a plausible genetic mechanism that warrants further investigation.