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Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes

An epistatic interaction between two genes occurs when the phenotypic impact of one gene depends on another gene, often exposing a functional association between them. Due to experimental scalability and to evolutionary significance, abundant work has been focused on studying how epistasis affects c...

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Autores principales: Snitkin, Evan S., Segrè, Daniel
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037399/
https://www.ncbi.nlm.nih.gov/pubmed/21347328
http://dx.doi.org/10.1371/journal.pgen.1001294
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author Snitkin, Evan S.
Segrè, Daniel
author_facet Snitkin, Evan S.
Segrè, Daniel
author_sort Snitkin, Evan S.
collection PubMed
description An epistatic interaction between two genes occurs when the phenotypic impact of one gene depends on another gene, often exposing a functional association between them. Due to experimental scalability and to evolutionary significance, abundant work has been focused on studying how epistasis affects cellular growth rate, most notably in yeast. However, epistasis likely influences many different phenotypes, affecting our capacity to understand cellular functions, biochemical networks adaptation, and genetic diseases. Despite its broad significance, the extent and nature of epistasis relative to different phenotypes remain fundamentally unexplored. Here we use genome-scale metabolic network modeling to investigate the extent and properties of epistatic interactions relative to multiple phenotypes. Specifically, using an experimentally refined stoichiometric model for Saccharomyces cerevisiae, we computed a three-dimensional matrix of epistatic interactions between any two enzyme gene deletions, with respect to all metabolic flux phenotypes. We found that the total number of epistatic interactions between enzymes increases rapidly as phenotypes are added, plateauing at approximately 80 phenotypes, to an overall connectivity that is roughly 8-fold larger than the one observed relative to growth alone. Looking at interactions across all phenotypes, we found that gene pairs interact incoherently relative to different phenotypes, i.e. antagonistically relative to some phenotypes and synergistically relative to others. Specific deletion-deletion-phenotype triplets can be explained metabolically, suggesting a highly informative role of multi-phenotype epistasis in mapping cellular functions. Finally, we found that genes involved in many interactions across multiple phenotypes are more highly expressed, evolve slower, and tend to be associated with diseases, indicating that the importance of genes is hidden in their total phenotypic impact. Our predictions indicate a pervasiveness of nonlinear effects in how genetic perturbations affect multiple metabolic phenotypes. The approaches and results reported could influence future efforts in understanding metabolic diseases and the role of biochemical regulation in the cell.
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spelling pubmed-30373992011-02-23 Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes Snitkin, Evan S. Segrè, Daniel PLoS Genet Research Article An epistatic interaction between two genes occurs when the phenotypic impact of one gene depends on another gene, often exposing a functional association between them. Due to experimental scalability and to evolutionary significance, abundant work has been focused on studying how epistasis affects cellular growth rate, most notably in yeast. However, epistasis likely influences many different phenotypes, affecting our capacity to understand cellular functions, biochemical networks adaptation, and genetic diseases. Despite its broad significance, the extent and nature of epistasis relative to different phenotypes remain fundamentally unexplored. Here we use genome-scale metabolic network modeling to investigate the extent and properties of epistatic interactions relative to multiple phenotypes. Specifically, using an experimentally refined stoichiometric model for Saccharomyces cerevisiae, we computed a three-dimensional matrix of epistatic interactions between any two enzyme gene deletions, with respect to all metabolic flux phenotypes. We found that the total number of epistatic interactions between enzymes increases rapidly as phenotypes are added, plateauing at approximately 80 phenotypes, to an overall connectivity that is roughly 8-fold larger than the one observed relative to growth alone. Looking at interactions across all phenotypes, we found that gene pairs interact incoherently relative to different phenotypes, i.e. antagonistically relative to some phenotypes and synergistically relative to others. Specific deletion-deletion-phenotype triplets can be explained metabolically, suggesting a highly informative role of multi-phenotype epistasis in mapping cellular functions. Finally, we found that genes involved in many interactions across multiple phenotypes are more highly expressed, evolve slower, and tend to be associated with diseases, indicating that the importance of genes is hidden in their total phenotypic impact. Our predictions indicate a pervasiveness of nonlinear effects in how genetic perturbations affect multiple metabolic phenotypes. The approaches and results reported could influence future efforts in understanding metabolic diseases and the role of biochemical regulation in the cell. Public Library of Science 2011-02-10 /pmc/articles/PMC3037399/ /pubmed/21347328 http://dx.doi.org/10.1371/journal.pgen.1001294 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Snitkin, Evan S.
Segrè, Daniel
Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title_full Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title_fullStr Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title_full_unstemmed Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title_short Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes
title_sort epistatic interaction maps relative to multiple metabolic phenotypes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037399/
https://www.ncbi.nlm.nih.gov/pubmed/21347328
http://dx.doi.org/10.1371/journal.pgen.1001294
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