Human brain evolution has played a pivotal role in the success of the human species, but it is also linked to an increased susceptibility to neurodevelopmental disorders such autism spectrum disorder (ASD) and neuropsychiatric disorders such as schizophrenia. Understanding the neural pathways involved with brain evolution are therefore likely to be very informative in developing an improved understanding of the pathogenesis of mental illness. In this context, evolutionary analyses may be an effective approach to investigating the complex genetic architecture of ASD.

Rare disruptive variants predisposing to ASD are under strong purifying selection (i.e., negative section: selective removal of deleterious alleles), consistent with a reduced fecundity observed in affected individuals. However, Renato Polimanti’s laboratory recently showed that some of the common variation associated with ASD is under positive selection (i.e., increase of allele frequency due to the favorable effect on individual fitness), possibly because of its involvement in neurogenesis and cognitive ability¹. These findings are in line with the positive effect of common polygenic ASD risk on cognitive ability previously reported in the general population². Accordingly, ASD common risk alleles could positively affect mechanisms related to neurogenesis, resulting in better cognitive ability. The evolutionary cost of an excessive burden of these risk variants is the onset of the developmental disorders included in the autism spectrum.

Building upon his laboratory’s previous findings and data regarding informative cohorts from the Simons Foundation Autism Research Initiative database (SFARI Base), the National Database for Autism Research (NDAR), the Database of Genotypes and Phenotypes (dbGaP), Polimanti now proposes to investigate 1) cognitive and social traits associated with ASD risk alleles under positive selection in affected and unaffected individuals; 2) brain activity associated with ASD risk alleles under positive selection in affected and unaffected individuals; 3) differences between affected and unaffected individuals in the associations observed. Understanding the consequences of these selected ASD risk alleles will provide novel insight regarding key mechanisms linking these risk alleles to both positive and negative cognitive and social traits, and help inform our understanding of the causes of ASD.