Protein complexes are central in the yeast genetic landscape

Abstract

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.

Figure 1. Monochromatic analysis overview.

We evaluate the monochromatic nature of biological processes (Within) and of the connections between processes (Between). Circles represent processes and links between them represent the set of SGA genetic interactions that connect genes within the processes. The color represents the monochromatic nature of the processes and connections (green is monochromatic positive, red is monochromatic negative, grey is non-monochromatic). We first define the processes and their connections and then evaluate their monochromatic nature. In the third step we remove various features, such as genes whose products are part of a complex and finally analyze the resulting change in monochromatic nature of the processes and connections.

Figure 2. Examples of monochromatic biological processes.

Circles represent genes and are labeled by the common gene name. Edges represent SGA genetic interactions between the genes. The color indicates the sign of the SGA score (green is positive, red is negative) and the width of the edge is proportional to the absolute value of the SGA score (epsilon) (the thicker the edge, the stronger the interaction). Biological processes are represented as four different networks labeled by the process name: ‘microautophagy’ and ‘histone exchange’ are monochromatic green, whereas ‘protein import’ and ‘small GTPase mediated signal transduction’ are monochromatic red. The networks were produced using Cytoscape .

Figure 3. Monochromatic processes are enriched in specific high-level functional categories.

The count of processes in each category is normalized by the background distribution for all processes. For example, 35 processes among all 2,501 yeast processes are in the category ‘protein degradation/proteasome’ in the background distribution whereas 3 among the 50 monochromatic processes are in that category, resulting in an enrichment ratio of 3/50 * 2501/35 = 4.3.

Figure 4. Protein complexes explain most monochromatic processes and connections.

A) Some monochromatic processes are no longer monochromatic when we remove the interactions occurring within complexes. Most monochromatic processes are no longer monochromatic when we remove the genes encoding proteins in complex. B) Half of the monochromatic connections are no longer monochromatic when we remove the interactions occurring within complexes. Most monochromatic connections are no longer monochromatic when we remove the genes encoding proteins in complex.