title: Genomewide landscape of gene-metabolome associations in Escherichia coli.
abstract: Metabolism is one of the best-understood cellular processes whose network topology of enzymatic reactions is determined by an organism's genome. The influence of genes on metabolite levels, however, remains largely unknown, particularly for the many genes encoding non-enzymatic proteins. Serendipitously, genomewide association studies explore the relationship between genetic variants and metabolite levels, but a comprehensive interaction network has remained elusive even for the simplest single-celled organisms. Here, we systematically mapped the association between > 3,800 single-gene deletions in the bacterium Escherichia coli and relative concentrations of > 7,000 intracellular metabolite ions. Beyond expected metabolic changes in the proximity to abolished enzyme activities, the association map reveals a largely unknown landscape of gene-metabolite interactions that are not represented in metabolic models. Therefore, the map provides a unique resource for assessing the genetic basis of metabolic changes and conversely hypothesizing metabolic consequences of genetic alterations. We illustrate this by predicting metabolism-related functions of 72 so far not annotated genes and by identifying key genes mediating the cellular response to environmental perturbations.
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Tobias
authors.identifier: 0000-0001-5006-6874
authors.initials: T
authors.lastname: Fuhrer
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Mattia
authors.initials: M
authors.lastname: Zampieri
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sévin
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland sauer@imsb.biol.ethz.ch.
authors.forename: Uwe
authors.identifier: 0000-0002-5923-0770
authors.initials: U
authors.lastname: Sauer
authors.affiliation: Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
authors.forename: Nicola
authors.identifier: 0000-0003-1271-1021
authors.initials: N
authors.lastname: Zamboni
mesh_terms: D004843:Epistasis, Genetic; D004926:Escherichia coli / Q000235:genetics*; D017353:Gene Deletion; D053263:Gene Regulatory Networks; D016680:Genome, Bacterial; D055106:Genome-Wide Association Study; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*
keywords: 
  GWAS
  ; functional genomics; interaction network; metabolism; metabolomics