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

  1. Mato Lagator
  2. Tiago Paixao
  3. Nick Barton
  4. Jonathan P Bollback
  5. Călin C Guet  Is a corresponding author
  1. Institute of Science and Technology Austria, 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.<strong> </strong>

Article and author information

Author details

  1. Mato Lagator

    Institute of Science and Technology Austria, klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  2. Tiago Paixao

    Institute of Science and Technology Austria, klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  3. Nick Barton

    Institute of Science and Technology Austria, klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan P Bollback

    Institute of Science and Technology Austria, klosterneuburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  5. Călin C Guet

    Institute of Science and Technology Austria, Klosterneuburg, Austria
    For correspondence
    calin@ist.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6220-2052

Funding

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.

Reviewing Editor

  1. Alvaro Sanchez, Yale University, United States

Publication history

  1. Received: January 16, 2017
  2. Accepted: May 17, 2017
  3. Accepted Manuscript published: May 18, 2017 (version 1)
  4. Version of Record published: June 22, 2017 (version 2)

Copyright

© 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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  1. Mato Lagator
  2. Tiago Paixao
  3. Nick Barton
  4. Jonathan P Bollback
  5. Călin C Guet
(2017)
On the mechanistic nature of epistasis in a canonical cis-regulatory element
eLife 6:e25192.
https://doi.org/10.7554/eLife.25192

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