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The E. coli Extended Genome

The E. coli Extended Genome. Fernando Baquero Dept. Microbiology, Ramón y Cajal University Hospital, and Laboratory for Microbial Evolution, CAB (INTA-CSIC) Madrid, Spain. The Species E. coli. Roles of the concept of “species”

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The E. coli Extended Genome

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  1. The E. coli Extended Genome Fernando Baquero Dept. Microbiology, Ramón y Cajal University Hospital, and Laboratory for Microbial Evolution, CAB (INTA-CSIC) Madrid, Spain

  2. The Species E. coli Roles of the concept of “species” • Units of taxonomic classification: Units in the general reference system that microbiologists use to order the isolates • Units of generalization: Kinds of microorganisms over which explanatory-predictive generalizations can be made • Units of evolution: Bacterial entities that participate in evolutionary processes and undergo evolutionary change (Modified from T.A.C. Reydon, Ph.D. Dissertation, Leiden University, 2005)

  3. New way The Species E. coli • Units of taxonomic classification: Units in the general reference system that microbiologists use to order the isolates • Units of generalization: Kinds of microorganisms over which explanatory-predictive generalizations can be made • Units of evolution: Bacterial entities that participate in evolutionary processes and undergo evolutionary change Classic way

  4. Diversity at all hierarchical levels Some strains are more mutable than others Strain Mutation Some populations tend to produce more clones? Population Clonalization Some bacterial groups tend to produce more species? Community Speciation At any level, the origin of diversity is probably stochastic

  5. Adaptation Complexity: MutationSingle adaptive event

  6. ClonalizationMultiple adaptive events

  7. SpeciationVerycomplex adaptive events

  8. Clonalization Allopatric clonalization Sympatric clonalization

  9. Host Defenses Clonalization ExPEC* Non-ExPEC Allopatric clonalization Sympatric clonalization * From James R. “Linneus” Johnson

  10. The elimination of intermediates Impossibility of being a business man and a little meermaid

  11. Species-Environment Concerted Evolution Phylogenetic groups Core genome Basic reproductive environment species evolution environmental evolution

  12. Co-evolution: Trees within Trees Host Bacteria or bacterial consortium

  13. The clues of E. coli genetic diversity • Errors in DNA replication and repair • Horizontal genetic transferfrom other organisms • Creation of mosaic genes from parts of other genes • Duplication and divergence of pre-existing genes • De novoinvention of genes from DNA that had previously a non-coding sequence Modified from Wolfe and Li, Nat. Genet. 33, 2003

  14. Not a single strain represents the whole species • K12-MG1655 (4,289 ORFs) • K12-W3110 (4,390 ORFs) • O157:H7 (Sakai) (5,361 ORFs) • O157:H7-EDL933 (5,349 ORFs) • E2348/69 • CFT073 (UPEC) (5,379 ORFs) • O42 (EAEC), HS, E24377A (ETEC), Nissle (PBEC) • Shigella floxneri SF-301 and 2457T (4,084)

  15. E. coli genomes 1,000 genes of difference! http://colibase.bham.ac.uk

  16. E. coli genomes http://colibase.bham.ac.uk

  17. Loops in a common core backbone A-strain B-strain A-loop (A-island) B-loops (B-islands)

  18. Loops in a common core backbone 296 loops in E. coli Sakai 325 loops in E. coli K12 A-strain B-strain BB: 3,730 kb BB: 3,730 kb 1,393 kb 537 kb S-loops K-loops

  19. Loop sizes Large loops arise from horizontal transfer events Small loops may arise from replication errors (small deletions or insertions), or correspond to highly polymorphic regions Chiapello et al., BMC Bioinformatics, 6:171, 2005

  20. The core backbone is not the minimal genome • The “core backbone” is not the “minimal E. coli genome”, because of high level of gene redundancy. • A high number of genesaremembers of gene families (2-30 copies), similar enough to be assigned similar functions (paralogs) • Such redundancy involves 20-40 % of the E. coli coding sequences (more in the largest genomes) • “In-silico metabolic phenotype” including all basic functions, predict about 700 genes in minimal genome(Blattner at al., Science 1997, Edwards and Palsson, PNAS 2000)

  21. Gogarden et Townsend, Nature Rev. Mic. (2005) The blue gene, unexpected in the species “C”, might have arisen: i) by horizontal gene transfer; or ii) by an ancient gene duplication followed by differential gene loss.

  22. The loops • The backbone evolves by vertical transfer. • Large loops are probably acquired by horizontal gene transfer, but also evolve by vertical transfer. • Loops tend to have a different codon usageand higher AT % than the backbone. • Loops tend to contain more frequently operational genes (actions) than informative genes (complex regulation) (R. Jain, 1999) PAIs, islets, phages, plasmids, transposable, repetitive elements...

  23. Random-scale sub-network (loop) ALIEN nodes Operative genes are more easily accepted links

  24. Elaboration from Jain et al. Scale free network (core) ALIEN nodes Informative genes less easily accepted Number of links (log)

  25. Elaboration from Jain et al. ALIEN Subnetwork Scale free network (core) Informative genes less easily accepted except alien replacement of an entire sub-network nodes Number of links (log)

  26. 3,256 E. coli genes are connected by 113,894 links Predicted functional modules in E. coli(von Mering et al., PNAS 100:15428, 2003)

  27. Loops as R&D E. coli laboratories Proteins expressed (bars in red) Positions of K-loops (bars in blue) The genes in the loops express proteins in only 10% of the cases M. Taoka et al., Mol & Cell. Proteomics (2004)

  28. Gene flux Excision Modification Acquisition Loss More loss in sequences of recent acquisition* Insertions and deletions occur more frequently in loops Overall less loss than acquisition? DuplicationModification (Daubin et al., Genome Biol., 4:R57, 2003; Ochman and Jones, EMBO J., 19:6637, 2000)

  29. Gene flux Acquisition Excision Modification ConstantRandom Gene Influx? Loss DuplicationModification As in the case of random mutation, there might be a blind, random uptake and loss of available foreign genetic sequences; environmental selection and random drift determines the fate of these constructions.

  30. E. coli- where alien genes come from? • Enterobacteriaceae (56 %) (Klebsiella, Salmonella, Serratia, Yersinia); Aeromonas, Xylella, Ralstonia, Caulobacter, Agrobacterium • Plasmids (28 %) - about 250 plasmids identified in E. coli. • Phages (10%) + many ORFan genes(64 MG1655-specific) (Modified from Duphraigne et al., NAR 33, 2005, and Daubin&Ochman, Genome Research, 2004) The E. coli “Gene Exchange Community” should be better identified!

  31. E. coli Recipient Barriers for Horizontal Gene Transfer • Ecological separation from donor • DNA sequence divergence • Low numbers • Inadequate phage receptors • Inadequate pilus specificity for mating • Contact-killing or inhibition • Surface exclusion • Restriction*; no anti-restriction mechanisms, gene inactivation • Absence of replication of foreign gene, incompatibility • Absence of integration of foreign gene in specific sites • No recombination with host genome (AT/CG), MMR system • Decrease in fitness of recipient after DNA acquisition • No more room for new DNA: Headroom (Maximal Genome?) *200 enzymes!

  32. Sequence divergence reduces acquisition of foreign DNA Modified from Gogarten and Towsend, Nature RM, 2005 Deleterious events are frequent with high divergence, but eventual beneficial events are rare with low divergence rates If the acquisition produce neutral events the tolerance increases

  33. Species-Environment Concerted Evolution Phylogenetic groups Core genome Basic reproductive environment species evolution environmental evolution

  34. Genome Size in E. coli strains ECOR Phylogenetic Groups kb K12 level Data: Bergthorsson and Ochman, Microb. Biol. Evol. 15:6-16, 1998

  35. Phylogenetic groups: clinical associations Clinical: Johnson et al., EID 11:141, 2005; Cystitis: Johnson et al., AAC 49:26, 2005; FUTI and rectal FUTI: Johnson et al., JCM 43:3895, 2005; Faecal Fr/Cr/Ma, Duriez et al., Microbiology 147:1671, 2001; Faecal HV Spain, Machado et al., AAC 49, 2005

  36. Phylogenetic groups: clinical associations Groups B2 and D are the more frequently found in E. coli bacteremia (Hilali et al., Inf.Imm 68:3983, 2000;Johnson et al., JID15:2121, 2004, Bingen, yesterday) But: “Epidemic extraintestinal strains”, many SxT-R in UTI in US, Israel, France (Johnson et al.,EID 11:141, 2005) Clinical: Johnson et al., EID 11:141, 2005; Cystitis: Johnson et al.,AAC 49:26, 2005; FUTI and rectal FUTI: Johnson et al., JCM 43:3895, 2005; Faecal Fr/Cr/Ma, Duriez et al., Microbiology 147:1671, 2001; Faecal HV Spain, Machado et al., AAC 49, 2005

  37. Distribution of E. coli isolates from hospitalized patients and fromhealthy volunteers among the four phylogenetic groups Machado, Cantón, Baquero et al., AAC 49 (2005) ESBLs (red) predominates among strains of group DPathogenic strains, non ESBL, predominates among group B2Commensal strains, non ESBL, predominates among group A

  38. Antimicrobial-R in phylogenetic groups SxT-R and Cipro-R(1): Johnson et al, AAC 49:26, 2005; ESBL: Machado et al., AAC 49, 2005; Cipro-R(2): Kuntaman et al., EID 11:1363, 2005 (Indonesia). The phylogenetic group B2, the more pathogenic one, tends to be the less resistant?

  39. Species-Environment Concerted Evolution Ecotypes Core genome Basic reproductive environment species evolution environmental evolution

  40. Models for Multiple Ecotypes (Gevers et al., Nature MR 3:733, 2005) Clonalization

  41. Patients with different ESBL clonesRamón y Cajal Hospital, Madrid (Baquero, Coque & Cantón, Lancet I.D. 2:591, 2002)

  42. Mutation: Intra-Clonal Diversity E. coli : Faecal - Urine - Blood - ESBLs Baquero et al, AAC 2004 and Nov. 2005

  43. Clonal Ensembles: Metastability through Intermittent Fixation Line of best fit clones time Different clones peak in frequency at different times, accordingly to the best-fit clone in each epoch* of a changing environment The maintenance of clonal ensembles is favored by the assymetry of fitness abilities in different clones in different epochs *epochal evolution Clonal ensemble

  44. Shared Environments and Maintenance of DiversityA regional polyclonal community structure 1 2 1 Alternative stable equilibria and the coexistence of variant organisms On this topic: Geographic mosaic theory of coevolution, Forde et al, Nature, 2004

  45. Maintenance of diversityA regional polyclonal community structure 1 2 1 Local Migration Local Gene Flow

  46. Diversity: Collapse and Resurrection Kin effects in open systems SELECTION

  47. Maintenance of diversityA regional polyclonal community structure 1 Environmental gradients are composed by a multiplicity of patches that may act as discrete selective points for bacterial variants

  48. Maintenance of diversityA regional polyclonal community structure Gradients and concentration-dependent selection (F. Baquero and C. Negri, Bioessays, 1997)

  49. Maintenance of Diversity by Scissors, Rock, Paper Model B. Kerr et al., Local dispersal promotes biodiversity in a real-life game of rock-paper-scissors. Nature 418:171, 2002

  50. Rock, Paper, Scissors Model 2. Scissors increase its power against paper... 3. And less paper means more stones... 1. If the stones reduces its attack again scissors....

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