title: Network of epistatic interactions within a yeast snoRNA.
abstract: Epistatic interactions play a fundamental role in molecular evolution, but little is known about the spatial distribution of these interactions within genes. To systematically survey a model landscape of intragenic epistasis, we quantified the fitness of ~60,000 Saccharomyces cerevisiae strains expressing randomly mutated variants of the 333-nucleotide-long U3 small nucleolar RNA (snoRNA). The fitness effects of individual mutations were correlated with evolutionary conservation and structural stability. Many mutations had small individual effects but had large effects in the context of additional mutations, which indicated negative epistasis. Clusters of negative interactions were explained by local thermodynamic threshold effects, whereas positive interactions were enriched among large-effect sites and between base-paired nucleotides. We conclude that high-throughput mapping of intragenic epistasis can identify key structural and functional features of macromolecules.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK.
authors.forename: Olga
authors.initials: O
authors.lastname: Puchta
authors.affiliation: School of Informatics, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Botond
authors.initials: B
authors.lastname: Cseke
authors.affiliation: Scott Tiger SA, Warsaw, Poland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Czaja
authors.affiliation: SynthSys, Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, Scotland, UK. Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: David
authors.initials: D
authors.lastname: Tollervey
authors.affiliation: School of Informatics, University of Edinburgh, Edinburgh, Scotland, UK. SynthSys, Centre for Synthetic and Systems Biology, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Guido
authors.initials: G
authors.lastname: Sanguinetti
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK. gkudla@gmail.com.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kudla
mesh_terms: D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D005800:Genes, Fungal; D014644:Genetic Variation; D016296:Mutagenesis; D009154:Mutation; D059370:RNA Folding; D020537:RNA, Small Nucleolar / Q000737:chemistry / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D013816:Thermodynamics
chemical_list: D020537:RNA, Small Nucleolar; C117378:RNA, U3 small nucleolar