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

Lagator, M, Paixão, T, Barton, NH, Bollback, JP ORCID: 0000-0002-4624-4612 and Guet, CC (2017) On the mechanistic nature of epistasis in a canonical cis-regulatory element. eLife, 6. e25192-.

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Official URL: https://elifesciences.org/articles/25192#abstract

Abstract

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 cis-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 cis-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.

Item Type:	Article
Uncontrolled Keywords:	Bacteriophage lambda, DNA, Epistasis, Genetic, Binding Sites, Phenotype, Mutation, Thermodynamics, Models, Biological, Regulatory Elements, Transcriptional
Depositing User:	Symplectic Admin
Date Deposited:	31 Jan 2018 07:50
Last Modified:	19 Jan 2023 06:46
DOI:	10.7554/elife.25192
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3014518