Two scientists at Stanford University in the United States say they have found a striking connection between how the human brain evolved over millions of years and why autism is relatively common in humans today, according to a study comparing the brains of different species.
The researchers focused on a specific type of neuron called L2/3 IT, found in the outer layers of the cerebral cortex, the brain region responsible for abstract thought and complex cognitive functions such as language, reasoning, memory and problem-solving.
In the study, published recently in the journal Molecular Biology and Evolution, the authors propose that, in general, the more common a neuron type is, the more slowly it evolves. They said this makes sense because mutations are an evolutionary gamble that can either bring advantages or cause harm to an organism.
However, the researchers identified an important exception to that rule: the L2/3 IT neurons, which are highly abundant in the cortex, changed faster in humans than in other primates such as chimpanzees and gorillas. The most surprising discovery was that hundreds of autism-linked genes changed in a coordinated way alongside this accelerated evolution, meaning that alterations which likely brought advantages to the human brain also increased its vulnerability to the disorder.
Why did brain evolution increase autism risk?
The observation, based on current evidence, that autism and schizophrenia are disorders exclusive to humans led to the scientific question that motivated the research: could evolutionary changes in L2/3 IT neurons explain humans' greater vulnerability to these conditions?
To test the hypothesis that any alteration in important and numerous cells raises the risk of serious consequences, the researchers analyzed single-nucleus RNA sequencing data from three distinct regions of the neocortex, covering six mammal species.
Working with three independent datasets, the team examined the gene expression of more than one million neurons, meaning which genes were active and producing proteins in each cell. The analysis confirmed the hypothesis that more common cell types are more genetically conserved.
Trying to confirm this principle, Alexander Starr and Hunter Fraser were surprised to find that layer 2/3 intratelencephalic excitatory neurons (L2/3 IT) evolved exceptionally fast in the human lineage, despite their high numbers and functional importance.
Yet this accelerated evolution coincided with a drastic reduction in the expression of 34 autism-linked genes. Although the change may have brought adaptive benefits, it also reduced the brain's safety margin, meaning alterations that would be harmless in other primates can cause autism in humans.
Key findings and possible future applications
By using modern single-cell transcriptomics techniques, which analyze the genes active in individual cells, the study combined evolution with neuroscience. The approach made it possible to identify how specific neurons, not just genetic sequences, changed over the course of evolution.
Beyond offering new perspectives on the human brain, the paper presents an evolutionary model for vulnerability to neuropsychiatric conditions such as autism and schizophrenia. The idea that changes in regulatory genes act as side effects links these conditions to the evolution of the brain itself.
This previously unrecognized relationship between cognitive innovation and risk suggests that certain conditions should be viewed as an integral part of human evolution rather than simply as defects. The concept of a evolutionary trade-off implies that greater benefits for certain human functions come at a price, namely the risk of autism.
In future biomedical research, the predictions of the model involving modified regulatory genes in L2/3 IT neurons could be tested experimentally in cells, organoids or animal models, opening the way for new therapies or biomarkers specific to autism.
Perhaps the study's greatest contribution is broadening the understanding of evolutionary neurodiversity, showing that brain differences, even those considered pathological, may have arisen from the same transformations that made the human brain unique over the course of evolutionary history.
