On the mechanistic nature of epistasis in a canonical cis-regulatory element
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.<strong> </strong>
Article and author information
Horizon 2020 Framework Programme (FP/2007-2013)
- Nick Barton
Seventh Framework Programme (FP7/2007-2013)
- Mato Lagator
Seventh Framework Programme (618091 (SAGE))
- Tiago Paixao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Alvaro Sanchez, Yale University, United States
- Received: January 16, 2017
- Accepted: May 17, 2017
- Accepted Manuscript published: May 18, 2017 (version 1)
- Version of Record published: June 22, 2017 (version 2)
© 2017, Lagator et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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