title: Non-essential genes form the hubs of genome scale protein function and environmental gene expression networks in Salmonella enterica serovar Typhimurium.
abstract: BACKGROUND
  Salmonella Typhimurium is an important pathogen of human and animals. It shows a broad growth range and survives in harsh conditions. The aim of this study was to analyze transcriptional responses to a number of growth and stress conditions as well as the relationship of metabolic pathways and/or cell functions at the genome-scale-level by network analysis, and further to explore whether highly connected genes (hubs) in these networks were essential for growth, stress adaptation and virulence.
  
  
  RESULTS
  De novo generated as well as published transcriptional data for 425 selected genes under a number of growth and stress conditions were used to construct a bipartite network connecting culture conditions and significantly regulated genes (transcriptional network). Also, a genome scale network was constructed for strain LT2. The latter connected genes with metabolic pathways and cellular functions. Both networks were shown to belong to the family of scale-free networks characterized by the presence of highly connected nodes or hubs which are genes whose transcription is regulated when responding to many of the assayed culture conditions or genes encoding products involved in a high number of metabolic pathways and cell functions.The five genes with most connections in the transcriptional network (wraB, ygaU, uspA, cbpA and osmC) and in the genome scale network (ychN, siiF (STM4262), yajD, ybeB and dcoC) were selected for mutations, however mutagenesis of ygaU and ybeB proved unsuccessful. No difference between mutants and the wild type strain was observed during growth at unfavorable temperatures, pH values, NaCl concentrations and in the presence of H2O2. Eight mutants were evaluated for virulence in C57/BL6 mice and none differed from the wild type strain. Notably, however, deviations of phenotypes with respect to the wild type were observed when combinations of these genes were deleted.
  
  
  CONCLUSIONS
  Network analysis revealed the presence of hubs in both transcriptional and functional networks of S. Typhimurium. Hubs theoretically confer higher resistance to random mutation but a greater susceptibility to directed attacks, however, we found that genes that formed hubs were dispensable for growth, stress adaptation and virulence, suggesting that evolution favors non-essential genes as main connectors in cellular networks.
authors.forename: Jesper T
authors.initials: JT
authors.lastname: Rosenkrantz
authors.forename: Henk
authors.initials: H
authors.lastname: Aarts
authors.forename: Tjakko
authors.initials: T
authors.lastname: Abee
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Rolfe
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Maj-Britt
authors.initials: MB
authors.lastname: Nielsen
authors.forename: Line E
authors.initials: LE
authors.lastname: Thomsen
authors.forename: Marcel H
authors.initials: MH
authors.lastname: Zwietering
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg, C, Denmark. jeo@sund.ku.dk.
authors.forename: John E
authors.initials: JE
authors.lastname: Olsen
authors.forename: Carmen
authors.initials: C
authors.lastname: Pin
mesh_terms: D000222:Adaptation, Physiological; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005798:Genes, Bacterial; D020043:Genes, Essential; D012486:Salmonella typhimurium / Q000235:genetics* / Q000502:physiology; D013312:Stress, Physiological; D014158:Transcription, Genetic