Summary: Researchers report that genetic variants associated with autism spectrum disorder (ASD) show evidence of positive selection during human evolution and may have contributed to enhanced cognitive traits.
Source: Yale.
New research indicates that some genetic variants linked to autism spectrum disorder may have been favored in human evolution because they also support higher cognitive ability.
A large genome-wide association study (GWAS) that included more than 5,000 ASD cases, combined with evolutionary analyses of gene selection, found that inherited variants associated with ASD appear under positive selection in greater numbers than expected by chance. The study argues these common variants, while increasing ASD risk, may also have conferred cognitive advantages that helped them persist through generations.
Large-effect variants that sharply reduce fertility or survival are usually eliminated by natural selection. In contrast, common variants that each have a modest effect can together shape complex inherited traits in meaningful ways. When the combined effect improves fitness or confers an advantage—such as enhanced cognitive capacity—those variants can persist and become more frequent in the population.
“We observed a clear positive selection signal among variants that are associated not only with ASD but also with measures of intellectual achievement,” said Renato Polimanti, associate research scientist at Yale School of Medicine and VA Connecticut Health Center and first author of the study. The results suggest a trade-off: alleles that promoted cognitive traits during human evolution may have increased the liability for ASD in some individuals.
Many of the positively selected ASD-associated variants identified by the investigators were enriched for molecular functions related to neurogenesis, including pathways involved in the formation and development of new neurons. This biological enrichment supports the idea that selection favored variants affecting brain development and function.
“It’s natural to ask why so many genetic variants that collectively contribute to ASD remain in human populations rather than being removed by selection,” said Joel Gelernter, Foundations Fund Professor of Psychiatry, professor of genetics and neuroscience, and co-author of the paper. “Our interpretation is that during human evolution, variants that improved cognitive abilities were selected for, even if they came at the cost of a higher risk for autism spectrum disorders in some genetic or environmental contexts.”
Funding: This research was supported by National Institutes of Health grants and a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation.
Source: Bill Hathaway, Yale.
Image source: NeuroscienceNews.com image used for illustration and noted as public domain in the original release.
Original research: Polimanti, R. & Gelernter, J. “Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder.” PLOS Genetics. Published online February 10, 2017. doi:10.1371/journal.pgen.1006618.
Yale, “Autism Risk Genes Linked to Evolving Brain.” NeuroscienceNews. Published February 27, 2017.
Abstract
Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder
The human brain is the product of complex evolutionary processes, and signatures of those processes may be detectable within the genetics of psychiatric and neurodevelopmental disorders. To explore this idea, the authors analyzed GWAS summary statistics for five psychiatric conditions—attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia—using data from the Psychiatric Genomics Consortium. Machine-learning–derived scores were applied to test two natural-selection scenarios: complete selection (where an advantageous allele reached fixation) and incomplete selection (where a selected allele has increased in frequency but not fixed).
ASD GWAS results showed a positive correlation with the incomplete-selection signal (p = 3.53 × 10−4). Variants with ASD GWAS p < 0.1 had a 19% greater probability of falling into the top 5% of incomplete-selection scores (OR = 1.19, 95% CI = 1.11–1.8, p = 9.56 × 10−7). Examining the direction of minor-allele effects revealed an enrichment of alleles with positive associations among SNPs with ASD GWAS p < 0.1 that also ranked in the top 5% for incomplete selection (permutation p < 10−4).
Focusing on this subset of ASD-associated, positively selected variants, the authors found gene-expression enrichments in brain and pituitary tissues (p = 2.3 × 10−5 and p = 3 × 10−5, respectively). Gene ontology analysis identified 53 enriched categories including nervous system development (GO:0007399, p = 7.57 × 10−12), synapse organization (GO:0050808, p = 8.29 × 10−7), and axon guidance (GO:0007411, p = 1.81 × 10−7). Previous genetic studies have reported positive correlations between ASD risk and measures such as childhood intelligence, college completion, and years of schooling. Taken together, these results support the hypothesis that some common ASD risk alleles show signatures of positive selection because they contributed to neurogenesis and cognitive traits during human evolution.
Polimanti, R. & Gelernter, J. “Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder.” PLOS Genetics. Published online February 10, 2017. doi:10.1371/journal.pgen.1006618.