TY - JOUR TI - Regulatory network structure determines patterns of intermolecular epistasis AU - Lagator, Mato AU - Sarikas, Srdjan AU - Acar, Hande AU - Bollback, Jonathan P AU - Guet, Călin C A2 - Wittkopp, Patricia J VL - 6 PY - 2017 DA - 2017/11/13 SP - e28921 C1 - eLife 2017;6:e28921 DO - 10.7554/eLife.28921 UR - https://doi.org/10.7554/eLife.28921 AB - 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. KW - distributions of mutational effects KW - epistasis KW - gene regulation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -