Autism may be the price of human brain evolution, study finds

What makes the human brain different from that of other primates has long been a question. A new study suggests that the answer may be in a surprising twist of evolutionary fate: one of the brain's most widespread forms of neurons developed quickly in humans, and the changes could explain why autism is so much more prevalent in humans compared to other animals.

The research highlights the ways in which natural selection drove our brains to make us smarter as humans but also drove us to be more prone to neurodevelopmental disorders.

It is widely known by biologists that genes that are used extensively in the body will evolve slowly, since harmful mutations can be extremely expensive. Scientists wondered if there was a corresponding rule for brain cells: would the most common neurons, which are centrally involved in brain activity, also evolve more slowly than common ones?

To determine this, the researchers studied enormous datasets constructed using single-nucleus RNA sequencing. The data provide information on which genes are turned on in a single brain cell. The researchers compared three parts of the mammalian neocortex—the medial temporal gyrus, dorsolateral prefrontal cortex, and primary motor cortex—across samples from humans, chimpanzees, monkeys, and other mammals.

Overall, there was a consistent pattern. The more common a neuron type was, the less its gene activity differed between species. This inverse correlation was seen in all brain regions studied with coefficients as great as –0.84 in a few cases. That is, shared neurons were more evolutionarily conserved.

That general rule did have one major exception, however. In people, one of the ubiquitous types of neurons, layer 2/3 intratelencephalic excitatory neurons—or L2/3 IT neurons—developed much more rapidly than expected. These cells are among the most abundant in the neocortex, the outermost part of the brain responsible for advanced thinking, reasoning, and language.

When researchers compared humans and chimpanzees, they found that the correlation between the number of neurons and evolutionary preservation nearly disappeared in the human lineage. The L2/3 IT neurons were to blame. After they removed them from the data set, the trend improved, suggesting that those neurons had diverged at an unusually rapid rate only in humans.

Other tests suggested that this wasn't just due to reduced evolutionary pressures. In fact, gene expression in L2/3 IT neurons was nicely regulated in humans, with less variance than in other primates. That pointed instead in the direction of positive selection—how these changes gave our ancestors an evolutionary advantage.

The second question was why these neurons had been developing so quickly. The answer may have a connection to autism. The researchers studied sets of genes strongly linked to autism spectrum disorder (ASD) and found an interesting pattern. In human L2/3 IT neurons, autism-linked genes were much more likely to be downregulated in expression than in chimpanzees.

In the medial temporal gyrus and dorsolateral prefrontal cortex, autism-related genes were down-regulated in humans at approximately fourfold over the predicted level. The same pattern was observed for schizophrenia-related genes but with weaker statistical evidence.

To determine whether these discrepancies were due to evolutionary forces and not sheer chance, the scientists used hybrid brain organoids grown from human and chimpanzee cells. Even here, under this same condition, human alleles of autism-linked genes were expressed more weakly than chimp alleles, confirming that the difference was etched into the DNA.

One of the examples given was the gene DLG4 that encodes the synaptic protein PSD-95. Human DLG4 was expressed at about half the rate in chimpanzees. The loss of a single copy of the gene leads to autism, so lowered expression of this gene is an important marker of evolutionary pressure.

The findings suggest that autism may not be just a disorder but also a component of the cost of being human. The hyperactivity of L2/3 IT neurons may have intensified skills like language, learning, or social cognition while at the same time amplifying susceptibility to autism.

Stanford University neuroscientist and senior author Alexander L. Starr put it this way: "Our results suggest that some of the same genetic changes that make the human brain unique also made humans more neurodiverse."

The study provides support to the long-standing theory that a few disorders are secondary byproducts of healthy evolutionary adaptations. The scientists compared it to how sickle cell anemia persists among certain populations because the same variant gene is a protection against malaria.

Non-human primates are almost unknown to have autism or schizophrenia. The researchers hypothesize this is because the diseases are linked to superior cognitive functions like talking, comprehension, and thinking abstractly—functions unique to humans. The researchers compared more than a million cells across six mammalian species to make sure that L2/3 IT neurons remained incredibly similar in the other primates. They changed only temporarily and selectively in humans.

The timing could also be why human beings develop more slowly after birth compared to other apes. Some of the genes linked with autism that are being favored are linked with developmental delays, suggesting that slower brain development gave human beings more time to acquire complex language and thinking skills.

Autism spectrum disorder currently affects an estimated one in 31 children in the United States and one in 100 worldwide, according to the CDC and World Health Organization. The vast majority of scientists estimate that up to 80 percent of cases can be traced to inherited genetic mutations.

The new study redefining autism not just as a disease but as a component of our species' evolution. Rather than considering autism purely medically, the findings show it is also linked with the very properties that make human intelligence.

The researchers caution, though, that their research makes correlation, not causation. Further studies will be needed to determine exactly how the genetic changes they outlined came to affect human traits. However, evidence for intense natural selection on autism-linked genes is hard to refute.

The study sheds light on how human disease and health are often linked to our evolutionary history. By providing the basis that autism risk may be a result of adaptations that made us distinctly human, the study can re-shape the approach scientists take to treating and diagnosing.

Understanding why such genetic variants arose may also direct novel therapies attempting to reconcile their benefits and drawbacks. The work could also result in an increased understanding of neurodiversity.

If traits linked with autism have a relationship with the beginnings of human intelligence and language, then inclusion of neurodiverse people is not only a medical problem but part of recognizing what makes humanity unique.

Research findings are available online in the journal Molecular Biology and Evolution.

Like these kind of feel good stories? Get The Brighter Side of News' newsletter.