Protein Complexes are Central in the Yeast Genetic Landscape

If perturbing two genes together has a stronger or weaker effect than expected, they are said to genetically interact. Genetic interactions are important because they help map gene function, and functionally related genes have similar genetic interaction patterns. Mapping quantitative (positive and negative) genetic interactions on a global scale has recently become possible. This data clearly shows groups of genes connected by predominantly positive or negative interactions, termed monochromatic groups. These groups often correspond to functional modules, like biological processes or complexes, or connections between modules. However it is not yet known how these patterns globally relate to known functional modules. Here we systematically study the monochromatic nature of known biological processes using the largest quantitative genetic interaction data set available, which includes fitness measurements for ∼5.4 million gene pairs in the yeast Saccharomyces cerevisiae. We find that only 10% of biological processes, as defined by Gene Ontology annotations, and less than 1% of inter-process connections are monochromatic. Further, we show that protein complexes are responsible for a surprisingly large fraction of these patterns. This suggests that complexes play a central role in shaping the monochromatic landscape of biological processes. Altogether this work shows that both positive and negative monochromatic patterns are found in known biological processes and in their connections and that protein complexes play an important role in these patterns. The monochromatic processes, complexes and connections we find chart a hierarchical and modular map of sensitive and redundant biological systems in the yeast cell that will be useful for gene function prediction and comparison across phenotypes and organisms. Furthermore the analysis methods we develop are applicable to other species for which genetic interactions will progressively become more available.

若同时扰动两个基因所产生的效应强于或弱于预期，则称二者发生遗传相互作用（genetic interaction）。遗传相互作用具有重要研究价值，因其可用于绘制基因功能图谱，且功能相关的基因往往具有相似的遗传相互作用模式。如今，全球范围内的定量（正向与负向）遗传相互作用图谱绘制已成为可能。该数据清晰展现了以正向或负向相互作用为主要连接方式的基因群，这类基因群被称为单色基因群（monochromatic group）。这类基因群通常对应功能模块，例如生物学过程或蛋白质复合物，或是模块间的连接关系。然而目前尚不清楚这些模式在全局层面如何与已知功能模块相关联。本研究利用现有最大规模的定量遗传相互作用数据集，系统性探究已知生物学过程的单色特征；该数据集涵盖酿酒酵母（Saccharomyces cerevisiae）中约540万对基因的适合度（fitness）测量数据。研究发现，按照基因本体论（Gene Ontology, GO）注释定义的生物学过程中，仅有10%的过程以及不足1%的过程间连接属于单色类型。此外，本研究证实蛋白质复合物在这类单色模式中占比惊人。这表明蛋白质复合物在塑造生物学过程的单色特征图谱中发挥核心作用。综上，本研究证实已知生物学过程及其连接关系中均存在正向与负向单色模式，且蛋白质复合物在这类模式中扮演重要角色。本研究发现的单色生物学过程、蛋白质复合物及连接关系，构建出酿酒酵母细胞内敏感与冗余生物系统的层级式模块化图谱，该图谱可用于基因功能预测以及不同表型与物种间的比较研究。此外，本研究开发的分析方法可推广至其他可逐步获取遗传相互作用数据的物种。