Adaptive evolution of genes underlying schizophrenia

Abstract

Schizophrenia poses an evolutionary-genetic paradox because it exhibits strongly negative fitness effects and high heritability, yet it persists at a prevalence of approximately 1% across all human cultures. Recent theory has proposed a resolution: that genetic liability to schizophrenia has evolved as a secondary consequence of selection for human cognitive traits. This hypothesis predicts that genes increasing the risk of this disorder have been subject to positive selection in the evolutionary history of humans and other primates. We evaluated this prediction using tests for recent selective sweeps in human populations and maximum-likelihood tests for selection during primate evolution. Significant evidence for positive selection was evident using one or both methods for 28 of 76 genes demonstrated to mediate liability to schizophrenia, including DISC1, DTNBP1 and NRG1, which exhibit especially strong and well-replicated functional and genetic links to this disorder. Strong evidence of non-neutral, accelerated evolution was found for DISC1, particularly for exon 2, the only coding region within the schizophrenia-associated haplotype. Additionally, genes associated with schizophrenia exhibited a statistically significant enrichment in their signals of positive selection in HapMap and PAML analyses of evolution along the human lineage, when compared with a control set of genes involved in neuronal activities. The selective forces underlying adaptive evolution of these genes remain largely unknown, but these findings provide convergent evidence consistent with the hypothesis that schizophrenia represents, in part, a maladaptive by-product of adaptive changes during human evolution.

Figure 1

Sliding-window analysis of DISC1 (disrupted in schizophrenia 1). A sliding-window analysis of DISC1 between humans and other primates identified several localized peaks of highly accelerated evolution. The most pronounced peaks (green arrows) co-localize to the HEP3 haplotype region, a region reproducibly shown to associate with schizophrenia. The locations of positively selected amino acid residues are indicated by red asterisks. Of the 16 selected residues, six fall within the HEP3 haplotype. Schematic of protein interaction domains within DISC1 are provided (Morris et al. 2003). A window size of 180 bp and a 3 bp sliding increment were used in the analysis.