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Network of Epistatic Interactions Within a Yeast snoRNA

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    Rights statement: This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Journal 352 (62887), DOI: 10.1126/science.aaf0965

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Original languageEnglish
Pages (from-to)840-844
Number of pages5
Issue number6287
Early online date14 Apr 2016
Publication statusPublished - 13 May 2016


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.

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