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Cited by 36Genomics and Phylogenetic StudiesBacterial Genetics and BiotechnologyEscherichia coli research studies

Gene-gene relationships in an Escherichia coli accessory genome are linked to function and mobility

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Hall, Rebecca J., Whelan, Fiona J., Cummins, Elizabeth A., Connor, Christopher, McNally, Alan, McInerney, James O.·2021·Microbial Genomics
DOI 10.1099/mgen.0.000650PMC PMC8715431

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Abstract

The pangenome contains all genes encoded by a species, with the core genome present in all strains and the accessory genome in only a subset. Coincident gene relationships are expected within the accessory genome, where the presence or absence of one gene is influenced by the presence or absence of another. Here, we analysed the accessory genome of an Escherichia coli pangenome consisting of 400 genomes from 20 sequence types to identify genes that display significant co-occurrence or avoidance patterns with one another. We present a complex network of genes that are either found together or that avoid one another more often than would be expected by chance, and show that these relationships vary by lineage. We demonstrate that genes co-occur by function, and that several highly connected gene relationships are linked to mobile genetic elements. We find that genes are more likely to co-occur with, rather than avoid, another gene in the accessory genome. This work furthers our understanding of the dynamic nature of prokaryote pangenomes and implicates both function and mobility as drivers of gene relationships.

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  • Testing whether an ancestral change in one trait consistently leads to the same change in the other trait would suggest the co-evolution is due to a causal link.

    “To distinguish which scenario is more likely, we could test whether an ancestral change in one trait consistently leads to the same change in the other trait, which would suggest the co-evolution is due to a causal link42,43,51,85–87 (Fig. 3).”

    From A phylogenetic approach to comparative genomics (2025) · cites this paper as [85]

    The Introduction discusses gene dependencies, and the Discussion reports repeated gene co-occurrence and avoidance in E. coli. Neither passage addresses testing the order of ancestral trait changes or whether a consistent sequence would indicate a causal link. Searches for ancestral changes, temporal order, and causal relationships found no passage making that point. (LLM, conf=0.72)

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Research works printed but not linked: 57

  1. [1]Goodall ECA Robinson A Johnston IG Jabbari S Turner KA et al The essential genome of Escherichia coli K-12 mBio 2018 9 02096 17 10.1128/mBio.02096-17 PMC5821084 29463657 · DOI
  2. [2]Pang TY Lercher MJ Each of 3,323 metabolic innovations in the evolution of E. coli arose through the horizontal transfer of a single DNA segment Proc Natl Acad Sci U S A 2019 116 187 192 10.1073/pnas.1718997115 30563853 PMC6320504 · DOI
  3. [3]Domingo-Sananes MR McInerney JO Mechanisms that shape microbial pangenomes Trends Microbiol 2021 29 493 503 10.1016/j.tim.2020.12.004 33423895 · DOI
  4. [4]Ogura Y Ooka T Iguchi A Toh H Asadulghani M et al Comparative genomics reveal the mechanism of the parallel evolution of O157 and non-O157 enterohemorrhagic Escherichia coli Proc Natl Acad Sci U S A 2009 106 17939 17944 10.1073/pnas.0903585106 19815525 PMC2764950 · DOI
  5. [5]Hentschel U Hacker J Pathogenicity islands: The tip of the iceberg Microbes Infect 2001 3 545 548 10.1016/s1286-4579(01)01410-1 11418328 · DOI
  6. [6]Johnson TJ Separate F-type plasmids have shaped the evolution of the H30 subclone of Escherichia coli sequence type 131 mSphere 2016 1 00121 16 PMC4933990 27390780
  7. [7]Nakamura K Murase K Sato MP Toyoda A Itoh T et al Differential dynamics and impacts of prophages and plasmids on the pangenome and virulence factor repertoires of Shiga toxin-producing Escherichia coli O145:H28 Microb Genom 2020 6 10.1099/mgen.0.000323 31935184 PMC7067040 · DOI
  8. [8]Bruns H Crüsemann M Letzel A-C Alanjary M McInerney JO et al Function-related replacement of bacterial siderophore pathways ISME J 2018 12 320 329 10.1038/ismej.2017.137 28809850 PMC5776446 · DOI
  9. [9]Rasko DA Rosovitz MJ Myers GSA Mongodin EF Fricke WF et al The pangenome structure of Escherichia coli: Comparative genomic analysis of E. coli commensal and pathogenic isolates J Bacteriol 2008 190 6881 6893 10.1128/JB.00619-08 18676672 PMC2566221 · DOI
  10. [10]Dobrindt U Patho-)Genomics of Escherichia coli Int J Med Microbiol 2005 295 357 371 10.1016/j.ijmm.2005.07.009 16238013 · DOI
  11. [11]Decano AG Downing T An Escherichia coli ST131 pangenome atlas reveals population structure and evolution across 4,071 isolates Sci Rep 2019 9 17394 10.1038/s41598-019-54004-5 31758048 PMC6874702 · DOI
  12. [12]Chen SL Hung C-S Xu J Reigstad CS Magrini V et al Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: A comparative genomics approach Proc Natl Acad Sci U S A 2006 103 5977 5982 10.1073/pnas.0600938103 16585510 PMC1424661 · DOI
  13. [13]Whelan FJ Rusilowicz M McInerney JO Coinfinder: Detecting significant associations and dissociations in pangenomes Microbial Genomics 2020 6 e000338 10.1099/mgen.0.000338 PMC7200068 32100706 · DOI · Paper page
  14. [14]Seemann T PROKKA: Rapid prokaryotic genome annotation Bioinformatics 2014 30 2068 2069 10.1093/bioinformatics/btu153 24642063 · DOI
  15. [15]Tonkin-Hill G MacAlasdair N Ruis C Weimann A Horesh G et al Producing polished prokaryotic pangenomes with the Panaroo pipeline Genome Biol 2020 21 180 10.1186/s13059-020-02090-4 32698896 PMC7376924 · DOI
  16. [16]Capella-Gutiérrez S Silla-Martínez JM Gabaldón T trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses Bioinformatics 2009 25 1972 1973 10.1093/bioinformatics/btp348 19505945 PMC2712344 · DOI
  17. [17]Nguyen L-T Schmidt HA von Haeseler A Minh BQ IQ-TREE: A fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies Mol Biol Evol 2015 32 268 274 10.1093/molbev/msu300 25371430 PMC4271533 · DOI · Paper page
  18. [18]Abadi S Azouri D Pupko T Mayrose I Model selection may not be a mandatory step for phylogeny reconstruction Nat Commun 2019 10 934 10.1038/s41467-019-08822-w 30804347 PMC6389923 · DOI
  19. [19]Letunic I Bork P Interactive Tree of Life (iTOL) v4: Recent updates and new developments Nucleic Acids Res 2019 47 W256 W259 10.1093/nar/gkz239 30931475 PMC6602468 · DOI
  20. [20]Whelan FJ Hall RJ McInerney JO Evidence for selection in the abundant accessory gene content of a prokaryote pangenome Mol Biol Evol 2021 10.1093/molbev/msab139 PMC8382901 33963386 · DOI · Paper page
  21. [21]The UniProt Consortium UNIPROT: The universal protein knowledge base Nucleic Acids Research 2017 45 PMC5861450 29425356
  22. [22]Kanehisa M Goto S KEGG: Kyoto Encyclopedia of Genes and Genomes Tech Rep 2000 1 PMC102409 10592173
  23. [23]Caspi R Altman T Billington R Dreher K Foerster H et al The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases Nucleic Acids Res 2014 42 D459 71 10.1093/nar/gkt1103 24225315 PMC3964957 · DOI · Paper page
  24. [24]Arredondo-Alonso S Rogers MRC Braat JC Verschuuren TD Top J et al mlplasmids: a user-friendly tool to predict plasmid- and chromosome-derived sequences for single species Microb Genom 2018 4 e000224 10.1099/mgen.0.000224 30383524 PMC6321875 · DOI
  25. [25]Page AJ Cummins CA Hunt M Wong VK Reuter S et al Roary: Rapid large-scale prokaryote pan genome analysis Bioinformatics 2015 31 3691 3693 10.1093/bioinformatics/btv421 26198102 PMC4817141 · DOI · Paper page
  26. [26]Kawasaki Y Wada C Yura T Roles of Escherichia coli heat shock proteins DnaK, DnaJ and GrpE in mini-F plasmid replication Molec Gen Genet 1990 220 277 282 10.1007/BF00260494 2183004 · DOI
  27. [27]Makino K Ishii K Yasunaga T Hattori M Yokoyama K et al Complete nucleotide sequences of 93-kb and 3.3-kb plasmids of an enterohemorrhagic Escherichia coli O157:H7 derived from Sakai outbreak DNA Res 1998 5 1 9 10.1093/dnares/5.1.1 9628576 · DOI
  28. [28]Schmidt H Beutin L Karch H Molecular analysis of the plasmid-encoded hemolysin of Escherichia coli O157:H7 strain EDL 933 Infect Immun 1995 63 1055 1061 10.1128/iai.63.3.1055-1061.1995 7868227 PMC173109 · DOI
  29. [29]Waldor MK Bacteriophage biology and bacterial virulence Trends Microbiol 1998 6 295 297 10.1016/s0966-842x(98)01320-1 9746936 · DOI
  30. [30]Handa N Kobayashi I Type III Restriction Is Alleviated by Bacteriophage (RecE) Homologous Recombination Function but Enhanced by Bacterial (RecBCD) Function J Bacteriol 2005 187 7362 7373 10.1128/JB.187.21.7362-7373.2005 16237019 PMC1272966 · DOI
  31. [31]Bachler C Schneider P Bahler P Lustig A Erni B Escherichia coli dihydroxyacetone kinase controls gene expression by binding to transcription factor DhaR EMBO J 2005 24 283 293 10.1038/sj.emboj.7600517 15616579 PMC545809 · DOI
  32. [32]Jenkins LS Nunn WD Genetic and molecular characterization of the genes involved in short-chain fatty acid degradation in Escherichia coli: The ATO system J Bacteriol 1987 169 42 52 10.1128/jb.169.1.42-52.1987 3025185 PMC211731 · DOI
  33. [33]Rome K Borde C Taher R Cayron J Lesterlin C et al The two-component system ZRAPSR is a novel ESR that contributes to intrinsic antibiotic tolerance in Escherichia coli J Mol Biol 2018 430 4971 4985 10.1016/j.jmb.2018.10.021 30389436 · DOI
  34. [34]Francetic O Belin D Badaut C Pugsley AP Expression of the endogenous type II secretion pathway in Escherichia coli leads to chitinase secretion EMBO Journal 2000 19 6697 6703 10.1093/emboj/19.24.6697 PMC305903 11118204 · DOI
  35. [35]Miki T Okada N Kim Y Abe A Danbara H DsbA directs efficient expression of outer membrane secretin EscC of the enteropathogenic Escherichia coli type III secretion apparatus Microb Pathog 2008 44 151 158 10.1016/j.micpath.2007.09.001 17933489 · DOI
  36. [36]Silver RP Aaronson W Vann WF The K1 capsular polysaccharide of Escherichia coli Rev Infect Dis 1988 10 Suppl 2 S282 6 10.1093/cid/10.supplement_2.s282 3055198 · DOI
  37. [37]Postma PW Lengeler JW Phosphoenolpyruvate: Carbohydrate phosphotransferase system of bacteria 1985 PMC373035 3900671
  38. [38]Tchieu JH Norris V Edwards JS Saier MH The complete phosphotransferase system in Escherichia coli J Mol Microbiol Biotechnol 2001 3 329 346 11361063
  39. [39]Manges AR Geum HM Guo A Edens TJ Fibke CD et al Global extraintestinal pathogenic Escherichia coli (ExPEC) lineages Clin Microbiol Rev 2019 32 10.1128/CMR.00135-18 PMC6589867 31189557 · DOI
  40. [40]Sokurenko EV Chesnokova V Dykhuizen DE Ofek I Wu XR et al Pathogenic adaptation of Escherichia coli by natural variation of the FIMH adhesin Proc Natl Acad Sci U S A 1998 95 8922 8926 10.1073/pnas.95.15.8922 9671780 PMC21178 · DOI
  41. [41]McNally A Diversification of colonization factors in a multidrug-resistant Escherichia coli lineage evolving under negative frequency- dependent selection mBio 2019 10 00644 19 PMC6479005 31015329
  42. [42]Rousset F The impact of genetic diversity on gene essentiality within the E. coli species bioRxiv 2020 33462433
  43. [43]McInerney JO McNally A O’Connell MJ Why prokaryotes have pangenomes Nature Microbiology 2017 2 1 5 28350002
  44. [44]Shapiro BJ The population genetics of pangenomes 2017 29176697
  45. [45]Andreani NA Hesse E Vos M Prokaryote genome fluidity is dependent on effective population size ISME Journal 2017 11 1719 1721 10.1038/ismej.2017.36 PMC5520154 28362722 · DOI
  46. [46]Lu Q-F Cao D-M Su L-L Li S-B Ye G-B et al Genus-wide comparative genomics analysis of Neisseria to identify new genes associated with pathogenicity and niche adaptation of Neisseria pathogens Int J Genomics 2019 2019 6015730 10.1155/2019/6015730 30775379 PMC6350579 · DOI
  47. [47]Didelot X Wilson DJ Clonalframeml: Efficient inference of recombination in whole bacterial genomes PLoS Comput Biol 2015 11 e1004041 10.1371/journal.pcbi.1004041 25675341 PMC4326465 · DOI
  48. [48]Cusumano CK Hung CS Chen SL Hultgren SJ Virulence plasmid harbored by uropathogenic Escherichia coli functions in acute stages of pathogenesis Infect Immun 2010 78 1457 1467 10.1128/IAI.01260-09 20123719 PMC2849428 · DOI
  49. [49]Kuenne C Reassessment of the Listeria monocytogenes pan-genome reveals dynamic integration hotspots and mobile genetic elements as major components of the accessory genome BMC Genomics 2013 14 47 10.1186/1471-2164-14-47 23339658 PMC3556495 · DOI
  50. [50]Firth N Skurray R Characterization of the F plasmid bifunctional conjugation gene, traG MGG Molecular & General Genetics 1992 232 145 153 1348105
  51. [51]Wallden K Rivera-Calzada A Waksman G Type IV secretion systems: Versatility and diversity in function 2010 PMC3070162 20642798
  52. [52]Schmidt H Henkel B Karch H A gene cluster closely related to type II secretion pathway operons of Gram-negative bacteria is located on the large plasmid of enterohemorrhagic Escherichia coli O157 strains FEMS Microbiology Letters 2006 148 265 272 10.1111/j.1574-6968.1997.tb10299.x 9084155 · DOI
  53. [53]Arciszewska L Sherratt D Xer site-specific recombination in vitro EMBO J 1995 14 2112 2120 7744017 PMC398313
  54. [55]Denamur E Clermont O Bonacorsi S Gordon D The population genetics of pathogenic Escherichia coli Nat Rev Microbiol 2020 19 37 54 10.1038/s41579-020-0416-x 32826992 · DOI
  55. [57]Zhang X First identification of coexistence of blaNDM-1 and bla CMY42 among Escherichia coli ST167 clinical isolates BMC Microbiol 2013 13 282 10.1186/1471-2180-13-282 24313961 PMC4029178 · DOI
  56. [58]Schaufler K Genomic and functional analysis of emerging virulent and multidrug-resistant Escherichia coli lineage sequence type 648 Antimicrob Agents Chemother 2019 63 10.1128/AAC.00243-19 30885899 PMC6535536 · DOI
  57. [59]Hibbing ME Dodson KW Kalas V Chen SL Hultgren SJ Adaptation of arginine synthesis among uropathogenic branches of the Escherichia coli phylogeny reveals adjustment to the urinary tract habitat mBio 2020 11 10.1128/mBio.02318-20 PMC7527732 32994329 · DOI

Cited by

Sorted by citations

Authors
Hall, R. J., Whelan, F. J., Cummins, E. A., Connor, C., McNally, A., & McInerney, J. O.
Affiliations
  • University of Nottingham (GB)
  • University of Birmingham (GB)
Corresponding author
McInerney, James O.
ORCID
Venue
Microbial Genomics
Publisher
Microbiology Society
Published
2021-09-09
Volume
7
Issue
9
ISSN
2057-5858 (ISSN-L)
DOI
10.1099/mgen.0.000650
PMC
PMC8715431
OpenAlex
W3196982248
Cited by
36
References
2
Citations by year
2026: 7 · 2025: 11 · 2024: 6 · 2023: 5 · 2022: 7
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Microbial Genomics (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
Funders
  • biotechnology and biological sciences research council (BB/N018044/2)
  • wellcome trust (Wellcome AAMR DTP, Wellcome Midas DTP)
  • h2020 marie skłodowska-curie actions (793818)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
Keywords
Escherichia coli, accessory genome, pan-genome, gene co-occurrence, gene co-occurrence networks, mobile genetic elements, gene mobility, bacterial lineages, core genome
MeSH terms
DNA Transposable Elements, Escherichia coli, Escherichia coli Infections, Genes, Bacterial, Phylogeny, Virulence, Genome, Bacterial, Evolution, Molecular

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