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.

中文翻译：

---

调节网络结构决定了分子间上位的模式

大多数表型是由特定相互作用的分子组成的分子系统决定的。然而，与单个组件不同的是，我们对分子系统作为一个整体的突变效应的分布知之甚少。我们询问转录调控系统的突变效应分布与其组成部分的分布有何不同，首先是独立地，然后是同时突变转录因子及其抑制的相关启动子。我们发现系统分布与单个组件分布相比表现出增加的表型变异 - 由转录因子与其 DNA 结合位点之间的分子间上位引起的影响。在很大程度上，这种上位性可以定性地归因于转录调控系统的结构，因此可能是原核生物的一个共同特征。与直觉相反，分子间上位性可以减轻单个组件的约束，从而增加选择可以作用的表型变异并促进适应性进化。