Did Evolution Make Humans Smarter — But More Prone To Autism?

Stanford findings suggest a human-specific trade-off between intelligence and vulnerability

STANFORD, Calif. — Natural selection shaped our most abundant brain cells so rapidly that the genetic changes may have enhanced human cognitive abilities while dramatically increasing autism risk, according to new research by Stanford University scientists.

In a study published in Molecular Biology and Evolution, researchers Alexander Starr and Hunter Fraser analyzed gene expression patterns across more than one million neurons from six mammal species. They discovered that “layer 2/3 intratelencephalic neurons,” the most common type of neuron in the human neocortex, evolved exceptionally quickly in our lineage compared to other apes.

These neurons enable communication between different brain regions and are thought to be important for uniquely human cognitive abilities. But the same rapid evolution that may have enhanced their function also appears to have made them hypersensitive to disruption.

“Surprisingly, this accelerated evolution was accompanied by the dramatic down-regulation of autism-associated genes, which was likely driven by polygenic positive selection specific to the human lineage,” researchers Alexander Starr and Hunter Fraser write in their paper.

The Abundance Principle

Starr and Fraser first established what they call a general principle of neuronal evolution: more abundant brain cell types evolve more slowly than rare ones.

This pattern makes biological sense. Changes to common neurons affect more of the brain, making harmful mutations more costly. Rarer cell types face less constraint because changes to them have smaller overall effects.

Despite being the most abundant neuronal type in the human neocortex, layer 2/3 IT neurons broke this rule.

When the researchers examined which genes changed most in these cells, they found something unexpected: 233 genes strongly linked to autism showed reduced activity in humans compared to chimpanzees.

The reduction was substantial. One gene that helps brain cells communicate had 2.5 times lower activity in humans than in chimpanzees. Losing just one working copy of this gene causes autism in humans. With human baseline activity already dramatically lower than in chimpanzees, humans may be operating much closer to a tipping point.

Consider a volume dial on a radio. Chimpanzees have it at 10. Losing one speaker (one gene copy) brings them down to 5, still functional. Humans already have the volume at 4. Losing one speaker drops them to 2, where the signal becomes too weak.

By lowering the baseline activity of autism-linked genes, human evolution may have brought us closer to the threshold where disruptions trigger autism.

Evidence for Natural Selection

To determine whether this gene activity reduction happened through natural selection or random chance, the researchers analyzed lab-grown brain tissue containing both human and chimpanzee DNA. This allowed them to directly compare how the two species’ genes behave in identical environments.

The results were most consistent with natural selection. Among autism-linked genes that differed between species, 27 out of 32 showed lower activity from the human version, a pattern inconsistent with random evolutionary change. The probability of this occurring by chance was less than 1%.

Several additional findings ruled out other explanations. Autism-linked genes showed no increase in harmful mutations in humans compared to chimpanzees. Activity of these genes was actually less variable among individual humans than among chimpanzees, suggesting stronger rather than weaker evolutionary pressure in our species.

While the evidence strongly favored natural selection, the researchers acknowledged they “cannot formally rule out other possible scenarios.”

Why Would Evolution Do This?

Among the possibilities, researchers propose that reducing activity of these genes may have provided evolutionary advantages to our ancestors, even though it increased vulnerability to autism.

What those advantages were remains unclear. The reduction may have contributed to the slower brain development after birth that’s characteristic of humans compared to other apes, allowing for extended learning periods. Alternatively, it might have enhanced capacity for language or other uniquely human abilities.

Another possibility is that the changes were compensatory, helping maintain optimal brain function in the face of other human-specific evolutionary changes like dramatic brain expansion or shifts in energy use.

Greater Vulnerability in Humans

Previous research has established that layer 2/3 IT neurons play a central role in autism. Studies examining individual cells have found these neurons are among the most affected in people with autism, showing altered gene activity patterns and disrupted protein interactions.

The Stanford findings suggest this vulnerability arose from evolutionary changes specific to humans. Large-scale genetic studies have found an excess of autism-linked variants in DNA sequences that evolved rapidly in our lineage. Brain imaging studies show that differences in brain wiring between humans and chimpanzees overlap with differences between humans with and without schizophrenia, a disorder that shares genetic overlap with autism.

Molecular evidence increasingly suggests autism may be more common in humans than in other primates, though direct behavioral comparisons across species remain challenging due to the difficulties in assessing complex social behaviors in different species.

Common Neurons, Higher Stakes

The new research provides a potential mechanism for this increased prevalence. The same evolutionary forces that made layer 2/3 IT neurons so abundant and functionally important also pushed their gene expression into a range where small additional changes can have outsized effects.

Most autism cases don’t result from a single catastrophic mutation but from the accumulation of many small genetic and environmental factors. By reducing the baseline activity of autism-linked genes, human evolution may have lowered the threshold at which these accumulated factors trigger autistic traits.

The research also revealed that this abundance-evolution relationship holds consistently across the mammalian brain. Analyzing three independent datasets covering different brain regions, the team found that more abundant cell types consistently showed greater conservation of gene activity between species.

More highly expressed genes and those with cell-type-specific expression patterns drove this correlation most strongly, suggesting that genes most critical to neuronal function face the strongest evolutionary constraints.

The pattern held across comparisons between humans and chimpanzees, gorillas, macaques, marmosets, and mice, across tens of millions of years of evolutionary divergence. Only comparisons between humans and non-human great apes showed weaker correlations, likely because of the rapid evolution the researchers identified in layer 2/3 IT neurons.

Future work from the Stanford team may reveal which human traits were shaped by these gene expression changes and why they came at the cost of greater vulnerability to disorders like autism. Understanding these evolutionary trade-offs could provide insight into both what makes human cognition unique and why certain neurodevelopmental disorders are more prevalent in our species than in other primates.

Disclaimer: This article is for general informational purposes only and is not medical advice. Autism is a complex condition influenced by many genetic and environmental factors. Readers should consult qualified professionals for health-related concerns.