On the mechanistic nature of epistasis in a canonical cis -regulatory element

• Published in: eLife 2017-05, Vol.6
• Main Authors: Lagator, Mato, Paixão, Tiago, Barton, Nicholas H, Bollback, Jonathan P, Guet, Călin C
• Format: Article
• Language: English
• Subjects: Bacteriophage lambda - genetics; Binding Sites; DNA - genetics; DNA sequencing; DNA-directed RNA polymerase; Earthquakes; Epistasis; Epistasis, Genetic; Gene expression; Gene regulation; Genomics and Evolutionary Biology; Genotype & phenotype; Metabolism; Methods; Models, Biological; Molecular modelling; Mutation; Observations; Phenotype; Regulatory Elements, Transcriptional; Thermodynamics; transcription
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.25192

Understanding the relation between genotype and phenotype remains a major challenge. The difficulty of predicting individual mutation effects, and particularly the interactions between them, has prevented the development of a comprehensive theory that links genotypic changes to their phenotypic effects. We show that a general thermodynamic framework for gene regulation, based on a biophysical understanding of protein-DNA binding, accurately predicts the sign of epistasis in a canonical -regulatory element consisting of overlapping RNA polymerase and repressor binding sites. Sign and magnitude of individual mutation effects are sufficient to predict the sign of epistasis and its environmental dependence. Thus, the thermodynamic model offers the correct null prediction for epistasis between mutations across DNA-binding sites. Our results indicate that a predictive theory for the effects of -regulatory mutations is possible from first principles, as long as the essential molecular mechanisms and the constraints these impose on a biological system are accounted for.