Regulatory network structure determines patterns of intermolecular epistasis Lagator, Mato Sarikas, Srdjan Acar, Hande ; https://orcid.org/0000-0003-1986-9753 Bollback, Jonathan P ; https://orcid.org/0000-0002-4624-4612 Guet, Calin C ; https://orcid.org/0000-0001-6220-2052 ddc:576 Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. eLife Sciences Publications 2017 info:eu-repo/semantics/article doc-type:article article http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/570 https://research-explorer.ista.ac.at/download/570/5096 https://research-explorer.ista.ac.at/download/570/5097 Lagator M, Sarikas S, Acar H, Bollback JP, Guet CC. Regulatory network structure determines patterns of intermolecular epistasis. <i>eLife</i>. 2017;6. doi:<a href="https://doi.org/10.7554/eLife.28921">10.7554/eLife.28921</a> eng info:eu-repo/semantics/altIdentifier/doi/10.7554/eLife.28921 info:eu-repo/semantics/altIdentifier/issn/2050-084X info:eu-repo/semantics/altIdentifier/wos/000425868200001 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess