Researchers at the Yale School of Medicine have found that genetic variants linked to autism spectrum disorder may have been positively selected for in human evolution, potentially explaining their continued presence in the human genome.

Published in the journal PLOS Genetics on Feb. 10, the study tested the presence of positive evolutionary selection in five psychiatric disorders: attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder and schizophrenia. The researchers found the strongest evidence in the genetics of autism spectrum disorder and discovered a correlation between ASD-associated genetic variants and genes involved in beneficial neural development.

“We observed that ASD-associated variations positively correlate with traits like childhood intelligence, college completion and years of schooling,” said Renato Polimanti, an associate research scientist at the medical school and the lead author on the study. “Under our hypothesis, ASD is the evolutionary cost of polygenic adaptation mechanisms related to cognitive ability.”

The study is part of a larger project supported by the Brain and Behavior Research Foundation, a nonprofit organization that funds research into the role of human evolution in shaping the genetics of psychiatric disorders. Such investigations are important, Polimanti said, because studying specific predispositions to mental illnesses throughout the evolution of the human brain can reveal the signatures of these evolutionary processes — common patterns in the way a particular gene has evolved.

“When disorders are maintained in the population, even though they are deleterious and interfere with reproductive fitness, it’s interesting to try to understand why variants with increased risks for these traits are nevertheless retained,” said Joel Gelernter ’79, a medical school psychiatry professor and a co-author on the study.

The researchers used two different types of data: association statistics from genome-wide association studies conducted by the Psychiatric Genomics Consortium and information regarding evolutionary selection signatures, which they derived from multiple tests for positive selection in the human genome.

They found that ASD-associated variations across the human genome, which affect thousands of genes, were positively selected for in larger numbers than would have been expected by chance.

Moreover, using the GWAS data, the scientists investigated whether the genetic mechanisms of ASD are shared across complex cognitive-related traits and calculated their genetic correlation. They determined that the genes with the evolutionary signatures were involved in molecular processes related to nervous system development, synapse organization and axon guidance.

With the positive correlation to traits such as childhood intelligence and college education level, the results indicate that having certain ASD-associated risk variants may have been beneficial during human evolutionary history, Polimanti said.

“We observed that ASD-risk variants across the human genome positively affect cognitive abilities,” Polimanti said. “However, those that carry too many of these genetic factors may develop the disease.”

According to Polimanti, the research confirms that ASD is a heritable disorder, and may even involve numerous variants affecting genes related to beneficial mechanisms.

The findings also provide a partial explanation for why variants that increase risk for ASD are retained. These same variants, on a population level, can improve intellectual ability and cognitive function, Gelernter said. However, certain combinations of these sets of variants can lead to ASD.

Gelernter added that the results make a substantial contribution to understanding the balancing pressure involved in genetic selection, in which an individual genetic variant can have both beneficial and deleterious effects.

Other than the genes investigated in this study, the sickle cell anemia risk allele is another example of a gene that can be both advantageous and harmful. Having one copy of the allele provides protection against malaria, but two copies result in sickle cell anemia, Gelernter said.

“These findings open a new perspective about the relationships among ASD, evolution and intelligence,” Polimanti said. “We plan to follow up our ASD findings, deepening our knowledge of the brain mechanisms related to the variants identified by analyzing both ASD cases and healthy controls.”

Polimanti said that as part of an ongoing project, the future study will also include investigating evolutionary mechanisms related to other mental illnesses.

According to the Centers for Disease Control and Prevention, about 1 in 68 children in the U.S. has been identified with some form of ASD.