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

ABSTRACT: Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes.

SUBMITTER: Gonzalez-Penas J

PROVIDER: S-EPMC10509162 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

González-Peñas Javier J de Hoyos Lucía L Díaz-Caneja Covadonga M CM Andreu-Bernabeu Álvaro Á Stella Carol C Gurriarán Xaquín X Fañanás Lourdes L Bobes Julio J González-Pinto Ana A Crespo-Facorro Benedicto B Martorell Lourdes L Vilella Elisabet E Muntané Gerard G Molto María Dolores MD Gonzalez-Piqueras Jose Carlos JC Parellada Mara M Arango Celso C Costas Javier J

Scientific reports 20230919 1

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positiv ...[more]

PMID: 37726359

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Project description:Antagonistic pleiotropy (AP), the ability of a gene to show opposing effects in different phenotypes, has been identified in various life history traits and complex disorders, indicating its fundamental role in balancing fitness over the course of evolution. It is intuitive that natural selection might maintain AP to allow organisms phenotypic flexibility in different environments. However, despite several attempts, little evidence exists for its role in adaptation. We performed a meta-analysis in yeast to identify the genetic basis of AP in bi-parental segregants, natural isolates, and a laboratory strain genome-wide deletion collection, by comparing growth in favorable and stress conditions. We found that whereas AP was abundant in the synthetic populations, it was absent in the natural isolates. This finding indicated resolution of trade-offs, i.e., mitigation of trade-offs over evolutionary history, probably through accumulation of compensatory mutations. In the deletion collection, organizational genes showed AP, suggesting ancient resolutions of trade-offs in the basic cellular pathways. We find abundant AP in the segregants, greater than estimated in the deletion collection or observed in previous studies, with IRA2, a negative regulator of the Ras/PKA signaling pathway, showing trade-offs across diverse environments. Additionally, IRA2 and several other Ras/PKA pathway genes showed balancing selection in isolates of S. cerevisiae and S. paradoxus, indicating that multiple alleles maintain AP in this pathway in natural populations. We propose that during AP resolution, retaining the ability to vary signaling pathways such as Ras/PKA, may provide organisms with phenotypic flexibility. However, with increasing organismal complexity AP resolution may become difficult. A partial resolution of AP could manifest as complex human diseases, and the inability to resolve AP may play a role in speciation. Our findings suggest that testing a universal phenomenon like AP across multiple experimental systems may elucidate mechanisms underlying its regulation and evolution.

Dataset Information

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

Publications

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

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