Network of epistatic interactions within a yeast snoRNA

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Science  14 Apr 2015:
DOI: 10.1126/science.aaf0965

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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-nt long U3 snoRNA. The fitness effects of individual mutations were correlated with evolutionary conservation and structural stability. Many mutations had small individual effects, but large effects in the context of additional mutations, indicating 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.

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