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Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell.

ABSTRACT: Dosage suppression is a genetic interaction in which overproduction of one gene rescues a mutant phenotype of another gene. Although dosage suppression is known to map functional connections among genes, the extent to which it might illuminate global cellular functions is unclear. Here we analyze a network of interactions linking dosage suppressors to 437 essential genes in yeast. For 424 genes, we curated interactions from the literature. Analyses revealed that many dosage suppression interactions occur between functionally related genes and that the majority do not overlap with other types of genetic or physical interactions. To confirm the generality of these network properties, we experimentally identified dosage suppressors for 29 genes from pooled populations of temperature-sensitive mutant cells transformed with a high-copy molecular-barcoded open reading frame library, MoBY-ORF 2.0. We classified 87% of the 1,640 total interactions into four general types of suppression mechanisms, which provided insight into their relative frequencies. This work suggests that integrating the results of dosage suppression studies with other interaction networks could generate insights into the functional wiring diagram of a cell.

SUBMITTER: Magtanong L

PROVIDER: S-EPMC7386433 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell.

Magtanong Leslie L Ho Cheuk Hei CH Barker Sarah L SL Jiao Wei W Baryshnikova Anastasia A Bahr Sondra S Smith Andrew M AM Heisler Lawrence E LE Choy John S JS Kuzmin Elena E Andrusiak Kerry K Kobylianski Anna A Li Zhijian Z Costanzo Michael M Basrai Munira A MA Giaever Guri G Nislow Corey C Andrews Brenda B Boone Charles C

Nature biotechnology 20110515 6

Dosage suppression is a genetic interaction in which overproduction of one gene rescues a mutant phenotype of another gene. Although dosage suppression is known to map functional connections among genes, the extent to which it might illuminate global cellular functions is unclear. Here we analyze a network of interactions linking dosage suppressors to 437 essential genes in yeast. For 424 genes, we curated interactions from the literature. Analyses revealed that many dosage suppression interacti ...[more]

PMID: 21572441

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Project description:MotivationIdentifying functional modules in protein-protein interaction (PPI) networks may shed light on cellular functional organization and thereafter underlying cellular mechanisms. Many existing module identification algorithms aim to detect densely connected groups of proteins as potential modules. However, based on this simple topological criterion of 'higher than expected connectivity', those algorithms may miss biologically meaningful modules of functional significance, in which proteins have similar interaction patterns to other proteins in networks but may not be densely connected to each other. A few blockmodel module identification algorithms have been proposed to address the problem but the lack of global optimum guarantee and the prohibitive computational complexity have been the bottleneck of their applications in real-world large-scale PPI networks.ResultsIn this article, we propose a novel optimization formulation LCP(2) (low two-hop conductance sets) using the concept of Markov random walk on graphs, which enables simultaneous identification of both dense and sparse modules based on protein interaction patterns in given networks through searching for LCP(2) by random walk. A spectral approximate algorithm SLCP(2) is derived to identify non-overlapping functional modules. Based on a bottom-up greedy strategy, we further extend LCP(2) to a new algorithm (greedy algorithm for LCP(2)) GLCP(2) to identify overlapping functional modules. We compare SLCP(2) and GLCP(2) with a range of state-of-the-art algorithms on synthetic networks and real-world PPI networks. The performance evaluation based on several criteria with respect to protein complex prediction, high level Gene Ontology term prediction and especially sparse module detection, has demonstrated that our algorithms based on searching for LCP(2) outperform all other compared algorithms.Availability and implementationAll data and code are available at http://www.cse.usf.edu/~xqian/fmi/slcp2hop/.

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Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell.

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Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell.

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