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


Author(s): Lagator, Mato; Paixão, Tiago; Barton, Nicholas H; Bollback, Jonathan P; Guet, Calin
Article Title: On the mechanistic nature of epistasis in a canonical cis-regulatory element
Affiliation IST Austria
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.
Journal Title: eLife Sciences
Volume: 6
ISSN: 2050-084X
Publisher: eLife Sciences Publications  
Date Published: 2017-05-18
Start Page: Article number: e25192
Copyright Statement: CC BY 4.0
URL:
DOI: 10.7554/eLife.25192.001
Notes: We thank H Acar, S Sarikas, and G Tkacik for discussion and useful comments on the manuscript. This work was supported by the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° [291734] to ML, has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 618091 (SAGE) to TP and European Research Council under the Horizon 2020 Framework Programme (FP/2007–2013) / ERC Grant Agreement n. [648440] to JPB.
Open access: yes (OA journal)