title: Differential regulation of antagonistic pleiotropy in synthetic and natural populations suggests its role in adaptation.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Radhakrishnan
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, 400005, India hsinha@tifr.res.in.
authors.forename: Himanshu
authors.identifier: http://orcid.org/0000-0001-7031-0491
authors.initials: H
authors.lastname: Sinha
mesh_terms: D000222:Adaptation, Physiological; D002874:Chromosome Mapping; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004843:Epistasis, Genetic; D017353:Gene Deletion; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D058685:Genetic Pleiotropy; D005828:Genetics, Population; D010641:Phenotype; D040641:Quantitative Trait Loci; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D018631:ras Proteins
keywords: QTL; Ras/PKA pathway; antagonistic pleiotropy; epistasis; gene−environment interaction