--- res: bibo_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.@eng bibo_authorlist: - foaf_Person: foaf_givenName: Mato foaf_name: Lagator, Mato foaf_surname: Lagator foaf_workInfoHomepage: http://www.librecat.org/personId=345D25EC-F248-11E8-B48F-1D18A9856A87 - foaf_Person: foaf_givenName: Tiago foaf_name: Paixao, Tiago foaf_surname: Paixao foaf_workInfoHomepage: http://www.librecat.org/personId=2C5658E6-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0003-2361-3953 - foaf_Person: foaf_givenName: Nicholas H foaf_name: Barton, Nicholas H foaf_surname: Barton foaf_workInfoHomepage: http://www.librecat.org/personId=4880FE40-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0002-8548-5240 - foaf_Person: foaf_givenName: Jonathan P foaf_name: Bollback, Jonathan P foaf_surname: Bollback foaf_workInfoHomepage: http://www.librecat.org/personId=2C6FA9CC-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0002-4624-4612 - foaf_Person: foaf_givenName: Calin C foaf_name: Guet, Calin C foaf_surname: Guet foaf_workInfoHomepage: http://www.librecat.org/personId=47F8433E-F248-11E8-B48F-1D18A9856A87 orcid: 0000-0001-6220-2052 bibo_doi: 10.7554/eLife.25192 bibo_volume: 6 dct_date: 2017^xs_gYear dct_identifier: - UT:000404024800001 dct_isPartOf: - http://id.crossref.org/issn/2050084X dct_language: eng dct_publisher: eLife Sciences Publications@ dct_title: On the mechanistic nature of epistasis in a canonical cis-regulatory element@ ...