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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.

SUBMITTER: Michaut M

PROVIDER: S-EPMC3044758 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Protein complexes are central in the yeast genetic landscape.

Michaut Magali M Baryshnikova Anastasia A Costanzo Michael M Myers Chad L CL Andrews Brenda J BJ Boone Charles C Bader Gary D GD

PLoS computational biology 20110224 2

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 monochromati ...[more]

PMID: 21390331

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Project description:Saccharomyces cerevisiae, whose evolutionary past includes a whole-genome duplication event, is characterized by a mosaic genome configuration with substantial apparent genetic redundancy. This apparent redundancy raises questions about the evolutionary driving force for genomic fixation of "minor" paralogs and complicates modular and combinatorial metabolic engineering strategies. While isoenzymes might be important in specific environments, they could be dispensable in controlled laboratory or industrial contexts. The present study explores the extent to which the genetic complexity of the central carbon metabolism (CCM) in S. cerevisiae, here defined as the combination of glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, and a limited number of related pathways and reactions, can be reduced by elimination of (iso)enzymes without major negative impacts on strain physiology. Cas9-mediated, groupwise deletion of 35 of the 111 genes yielded a "minimal CCM" strain which, despite the elimination of 32% of CCM-related proteins, showed only a minimal change in phenotype on glucose-containing synthetic medium in controlled bioreactor cultures relative to a congenic reference strain. Analysis under a wide range of other growth and stress conditions revealed remarkably few phenotypic changes from the reduction of genetic complexity. Still, a well-documented context-dependent role of GPD1 in osmotolerance was confirmed. The minimal CCM strain provides a model system for further research into genetic redundancy of yeast genes and a platform for strategies aimed at large-scale, combinatorial remodeling of yeast CCM. IMPORTANCE Fundamental questions regarding the minimal requirements for life have prompted scientists to embark on top-down efforts to reduce microbial genomes to the minimum set of genes and proteins necessary to sustain cell survival and division. While these efforts are generally focused on small, prokaryotic genomes, Saccharomyces cerevisiae, a popular industrial and model organism, has a typical eukaryotic genome characterized by a high genetic redundancy. The cellular function of redundant genes is generally poorly understood and is often investigated at the scale of a few genes. In this study, we explore genetic redundancy at large scale, encompassing the ~100 genes involved in central carbon metabolism, a part of metabolism essential for life and highly conserved among eukaryotes. This study reveals the remarkable resilience of this model eukaryote, as it was hardly affected, under a broad range of conditions, by a 32% reduction of its central carbon metabolism.

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Protein complexes are central in the yeast genetic landscape.

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Protein complexes are central in the yeast genetic landscape.

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