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.

大多数表型由特异性相互作用的分子组成的分子系统决定。但是，与单个组件不同，关于分子系统整体的突变效应的分布知之甚少。我们问一个转录调节系统的突变作用的分布与它的组成部分的分布有何不同，首先独立地，然后同时使突变的转录因子和它所抑制的相关启动子发生变化。我们发现，与单个成分分布相比，系统分布表现出增加的表型变异-一种转录因子与其DNA结合位点之间的分子间上位性引起的效应。在很大程度上，这种上位性可以归因于转录调节系统的结构，因此可能是原核生物的共同特征。与直觉相反，分子间上皮可以减轻单个成分的约束，从而增加选择可能作用的表型变异并促进适应性进化。