Recent natural selection conferred protection against schizophrenia by non-antagonistic pleiotropy

Area of Science:

• Evolutionary biology
• Psychiatric genetics
• Human population genetics

Background:

• Schizophrenia presents an evolutionary paradox due to reduced fertility and lifespan despite significant genetic contributions.
• Previous explanations like balanced selection are increasingly challenged by evidence against positive selection of risk alleles.
• Evolutionary pressures on schizophrenia risk alleles may have shifted with changing human environments.

Purpose of the Study:

• To investigate the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures.
• To explore the role of RNS in the persistence of schizophrenia-associated genetic variation after human migration out of Africa.

Main Methods:

• Genome-wide analysis of 1000 Genomes Project data.
• Identification and analysis of recent natural selection (RNS) markers.
• Partitioned heritability and gene set enrichment analyses of schizophrenia predisposing loci.

Main Results:

• Significant enrichment of RNS markers was found in derived alleles that confer protection against schizophrenia.
• Genes associated with schizophrenia risk loci under RNS showed reduced involvement in brain and neuronal functions compared to those not under RNS.
• Evidence suggests RNS is linked to non-psychiatric phenotypes.

Conclusions:

• Recent natural selection (RNS) may explain the persistence of schizophrenia predisposing variation.
• Non-antagonistic pleiotropy is proposed as the underlying mechanism, where RNS affects protective non-psychiatric traits.
• This resolves the evolutionary paradox of schizophrenia's common genetic variation.