Abstract
Descriptions of genes that are adaptively evolving in humans and that carry polymorphisms with an effect on cognitive performances have been virtually absent. SNAP25 encodes a presynaptic protein with a role in regulation of neurotransmitter release. We analysed the intra-specific diversity along SNAP25 and identified a region in intron 1 that shows signatures of balancing selection in humans. The estimated TMRCA (time to the most recent common ancestor) of the SNAP25 haplotype phylogeny amounted to 2.08 million years. The balancing selection signature is not secondary to demographic events or to biased gene conversion, and encompasses rs363039. This SNP has previously been associated to cognitive performances with contrasting results in different populations. We analysed this variant in two Italian cohorts in different age ranges and observed a significant genotype effect for rs363039 on verbal performances in females alone. Post hoc analysis revealed that the effect is driven by differences between heterozygotes and both homozygous genotypes. Thus, heterozygote females for rs363039 display higher verbal performances compared to both homozygotes. This finding was replicated in a cohort of Italian subjects suffering from neuromuscular diseases that do not affect cognition. Heterozygote advantage is one of the possible reasons underlying the maintenance of genetic diversity in natural populations. The observation that heterozygotes for rs363039 display higher verbal abilities compared to homozygotes perfectly fits the underlying balancing selection model. Although caution should be used in inferring selective pressures from observed signatures, SNAP25 might represent the first description of an adaptively evolving gene with a role in cognition.