What sets the human brain apart from those of other primates has been a long-standing question in neuroscience. A groundbreaking study now suggests that a twist in evolutionary development may hold the answer: a specific type of neuron in the human brain evolved rapidly, potentially explaining why autism is more prevalent in humans compared to other animals.
The research underscores how natural selection has shaped our brains to enhance intelligence and cognitive abilities, while also increasing susceptibility to neurodevelopmental disorders.
Neurons, Genes, and Evolutionary Patterns
Biologists have long understood that genes extensively used in the body evolve slowly, as harmful mutations can be costly. This principle led scientists to question whether a similar rule applies to brain cells: do the most common neurons, which play central roles in brain activity, evolve more slowly than others?
To explore this, researchers analyzed vast datasets using single-nucleus RNA sequencing, which reveals which genes are active in individual brain cells. They compared three regions of the mammalian neocortex—the medial temporal gyrus, dorsolateral prefrontal cortex, and primary motor cortex—across samples from humans, chimpanzees, monkeys, and other mammals.
The findings showed a consistent pattern: the more prevalent a neuron type, the less its gene activity varied between species. This inverse correlation was evident in all brain regions studied, with coefficients reaching as high as –0.84 in some cases, indicating that common neurons were evolutionarily conserved.
The Outlier: Rapid Evolution in Human Neurons
However, this general rule had a notable exception. In humans, a type of neuron known as layer 2/3 intratelencephalic excitatory neurons (L2/3 IT neurons) evolved much more rapidly than anticipated. These neurons are abundant in the neocortex, which is responsible for advanced cognitive functions such as reasoning and language.
Comparisons between humans and chimpanzees revealed that the correlation between neuron abundance and evolutionary conservation nearly vanished in humans, primarily due to the rapid evolution of L2/3 IT neurons. When these neurons were excluded from the analysis, the trend improved, suggesting their unique evolutionary trajectory in humans.
Further tests indicated that this rapid evolution was not merely due to reduced evolutionary pressures. In fact, gene expression in human L2/3 IT neurons was well-regulated, with less variance than in other primates. This pointed to positive selection, implying that these changes provided an evolutionary advantage to our ancestors.
Autism-Linked Genes Take Center Stage
The next question was why these neurons evolved so quickly. The answer may lie in a connection to autism. Researchers examined genes strongly linked to autism spectrum disorder (ASD) and discovered a compelling pattern. In human L2/3 IT neurons, autism-related genes were more likely to be downregulated compared to chimpanzees.
In the medial temporal gyrus and dorsolateral prefrontal cortex, autism-linked genes were downregulated in humans at approximately four times the expected level. A similar pattern was observed for schizophrenia-related genes, albeit with weaker statistical evidence.
To confirm these discrepancies were due to evolutionary forces rather than chance, scientists used hybrid brain organoids grown from human and chimpanzee cells. Even under these conditions, human alleles of autism-linked genes were expressed more weakly than chimp alleles, indicating that the differences were embedded in the DNA.
One notable example is the gene DLG4, which encodes the synaptic protein PSD-95. Human DLG4 expression was about half that in chimpanzees. The loss of a single copy of this gene leads to autism, making its reduced expression a significant marker of evolutionary pressure.
Autism as a Trade-Off in Human Evolution
The findings suggest that autism may not solely be a disorder but also a consequence of human evolution. The heightened activity of L2/3 IT neurons may have enhanced skills such as language, learning, and social cognition, while simultaneously increasing vulnerability to autism.
Stanford University neuroscientist and senior author Alexander L. Starr commented, “Our results suggest that some of the same genetic changes that make the human brain unique also made humans more neurodiverse.”
This study supports the theory that certain disorders are byproducts of evolutionary adaptations. The researchers compared it to how sickle cell anemia persists in certain populations because the same gene variant provides protection against malaria.
Why Humans, and Not Other Primates?
Autism and schizophrenia are almost unheard of in non-human primates. Researchers hypothesize this is because these conditions are linked to advanced cognitive functions like language, comprehension, and abstract thinking—traits unique to humans. The study compared over a million cells across six mammalian species, confirming that L2/3 IT neurons remained remarkably similar in other primates, changing only in humans.
The timing of these changes might also explain why humans develop more slowly after birth compared to other apes. Some autism-linked genes are associated with developmental delays, suggesting that slower brain development allowed humans more time to acquire complex language and cognitive skills.
Rethinking Autism Through an Evolutionary Lens
According to the CDC and World Health Organization, autism spectrum disorder currently affects an estimated one in 31 children in the United States and one in 100 worldwide. Most scientists estimate that up to 80 percent of cases can be traced to inherited genetic mutations.
This new study redefines autism not just as a disease but as a component of human evolution. Rather than viewing autism purely as a medical condition, the findings suggest it is linked to the very traits that define human intelligence.
Researchers caution, however, that their study establishes correlation, not causation. Further research is needed to determine precisely how these genetic changes influence human traits. Nonetheless, the evidence for intense natural selection on autism-linked genes is compelling.
Practical Implications of the Research
This study sheds light on how human health and disease are often intertwined with our evolutionary history. By suggesting that autism risk may be a result of adaptations that made us uniquely human, the research could reshape approaches to treatment and diagnosis.
Understanding why such genetic variants arose may also guide new therapies that balance their benefits and drawbacks. The work could lead to a greater appreciation of neurodiversity.
If traits associated with autism are linked to the origins of human intelligence and language, then embracing neurodiversity is not only a medical issue but also part of recognizing what makes us uniquely human.
The research findings are available online in the journal Molecular Biology and Evolution.
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