Puchta Olga, Cseke Botond, Czaja Hubert, Tollervey David, Sanguinetti Guido, Kudla Grzegorz
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, Scotland, UK.
School of Informatics, University of Edinburgh, Edinburgh, Scotland, UK.
Science. 2016 May 13;352(6287):840-4. doi: 10.1126/science.aaf0965. Epub 2016 Apr 14.
Epistatic interactions play a fundamental role in molecular evolution, but little is known about the spatial distribution of these interactions within genes. To systematically survey a model landscape of intragenic epistasis, we quantified the fitness of ~60,000 Saccharomyces cerevisiae strains expressing randomly mutated variants of the 333-nucleotide-long U3 small nucleolar RNA (snoRNA). The fitness effects of individual mutations were correlated with evolutionary conservation and structural stability. Many mutations had small individual effects but had large effects in the context of additional mutations, which indicated negative epistasis. Clusters of negative interactions were explained by local thermodynamic threshold effects, whereas positive interactions were enriched among large-effect sites and between base-paired nucleotides. We conclude that high-throughput mapping of intragenic epistasis can identify key structural and functional features of macromolecules.
上位性相互作用在分子进化中起着根本性作用，但对于这些相互作用在基因内的空间分布却知之甚少。为了系统地探究基因内上位性的模型格局，我们对约60000株表达333个核苷酸长的U3小核仁RNA（snoRNA）随机突变变体的酿酒酵母菌株的适应性进行了量化。单个突变的适应性效应与进化保守性和结构稳定性相关。许多突变的个体效应较小，但在其他突变的背景下具有较大效应，这表明存在负上位性。负相互作用簇可由局部热力学阈值效应解释，而正相互作用在大效应位点之间以及碱基配对核苷酸之间富集。我们得出结论，基因内上位性的高通量图谱绘制能够识别大分子的关键结构和功能特征。
