Plasmids have a key role in bacterial ecology and evolution because they mobilize accessory genes by horizontal gene transfer. However, recent studies have revealed that the evolutionary impact of plasmids goes above and beyond their being mere gene delivery platforms. Plasmids are usually kept at multiple copies per cell, producing islands of polyploidy in the bacterial genome. As a consequence, the evolution of plasmid-encoded genes is governed by a set of rules different from those affecting chromosomal genes, and these rules are shaped by unusual concepts in bacterial genetics, such as genetic dominance, heteroplasmy or segregational drift. In this Review, we discuss recent advances that underscore the importance of plasmids in bacterial ecology and evolution beyond horizontal gene transfer. We focus on new evidence that suggests that plasmids might accelerate bacterial evolution, mainly by promoting the evolution of plasmid-encoded genes, but also by enhancing the adaptation of their host chromosome. Finally, we integrate the most relevant theoretical and empirical studies providing a global understanding of the forces that govern plasmid-mediated evolution in bacteria.
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Lederberg, J. Cell genetics and hereditary symbiosis. Physiol. Rev. 32, 403–430 (1952). A landmark article in which the term ‘plasmid’ is proposed for the first time.
Lederberg, J. Personal perspective: plasmid (1952-1997). Plasmid 39, 1–9 (1998).
Werren, J. H. Selfish genetic elements, genetic conflict, and evolutionary innovation. Proc. Natl Acad. Sci. USA 108, 10863–10870 (2011).
Rankin, D. J., Rocha, E. P. C. & Brown, S. P. What traits are carried on mobile genetic elements, and why. Heredity 106, 1–10 (2011).
Hernández-Arriaga, A. M., Chan, W. T., Espinosa, M. & Díaz-Orejas, R. Conditional activation of toxin-antitoxin systems: postsegregational killing and beyond. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.PLAS-0009-2013 (2014).
Norman, A., Hansen, L. H. & Sørensen, S. J. Conjugative plasmids: vessels of the communal gene pool. Philos. Trans. R. Soc. B Biol. Sci. 364, 2275–2289 (2009).
Ramsay, J. P. et al. An updated view of plasmid conjugation and mobilization in Staphylococcus. Mob. Genet. Elem. 6, e1208317 (2016).
Carattoli, A. et al. Identification of plasmids by PCR-based replicon typing. J. Microbiol. Methods 63, 219–228 (2005).
Smillie, C., Garcillán-Barcia, M. P., Francia, M. V., Rocha, E. P. C. & de la Cruz, F. Mobility of plasmids. Microbiol. Mol. Biol. Rev. 74, 434–452 (2010). A thorough analysis of plasmid mobility that sets the basis for mobility typing.
Douarre, P.-E., Mallet, L., Radomski, N., Felten, A. & Mistou, M.-Y. Analysis of COMPASS, a new comprehensive plasmid database revealed prevalence of multireplicon and extensive diversity of IncF plasmids. Front. Microbiol. 11, 1–15 (2020).
Acman, M., van Dorp, L., Santini, J. M. & Balloux, F. Large-scale network analysis captures biological features of bacterial plasmids. Nat. Commun. 11, 2452 (2020). A comprehensive analysis of plasmid whole-genome sequences using similarity networks that paves the way for novel plasmid classification schemes.
Redondo-Salvo, S. et al. Pathways for horizontal gene transfer in bacteria revealed by a global map of their plasmids. Nat. Commun. 11, 3602 (2020).
Szpirer, C., Top, E., Couturier, M. & Mergeay, M. Retrotransfer or gene capture: a feature of conjugative plasmids, with ecological and evolutionary significance. Microbiology 145, 3321–3329 (1999).
Tock, M. R. & Dryden, D. T. F. The biology of restriction and anti-restriction. Curr. Opin. Microbiol. 8, 466–472 (2005).
Pinilla-Redondo, R. et al. Type IV CRISPR-Cas systems are highly diverse and involved in competition between plasmids. Nucleic Acids Res. 48, 2000–2012 (2020).
Ares-Arroyo, M. et al. PCR-based analysis of ColE1 plasmids in clinical isolates and metagenomic samples reveals their importance as gene capture platforms. Front. Microbiol. 9, 469 (2018).
Attéré, S. A., Vincent, A. T., Paccaud, M., Frenette, M. & Charette, S. J. The role for the small cryptic plasmids as moldable vectors for genetic innovation in Aeromonas salmonicida subsp. salmonicida. Front. Genet. 8, 1–11 (2017).
Pilla, G. & Tang, C. M. Going around in circles: Virulence plasmids in enteric pathogens. Nat. Rev. Microbiol. 16, 484–495 (2018).
Carattoli, A. Resistance plasmid families in Enterobacteriaceae. Antimicrob. Agents Chemother. 53, 2227–2238 (2009).
Brinkmann, H., Göker, M., Koblížek, M., Wagner-Döbler, I. & Petersen, J. Horizontal operon transfer, plasmids, and the evolution of photosynthesis in Rhodobacteraceae. ISME J. 12, 1994–2010 (2018).
Manzano-Marıˊn, A. et al. Serial horizontal transfer of vitamin-biosynthetic genes enables the establishment of new nutritional symbionts in aphids’ di-symbiotic systems. ISME J. 14, 259–273 (2020).
Anda, M. et al. Bacterial clade with the ribosomal RNA operon on a small plasmid rather than the chromosome. Proc. Natl Acad. Sci. USA 112, 14343–14347 (2015). An example of an HCP carrying an essential core gene for its bacterial host.
Wang, X. et al. Comparative symbiotic plasmid analysis indicates that symbiosis gene ancestor type affects plasmid genetic evolution. Lett. Appl. Microbiol. 67, 22–31 (2018).
Soucy, S. M., Huang, J. & Gogarten, J. P. Horizontal gene transfer: building the web of life. Nat. Rev. Genet. 16, 472–482 (2015).
Vos, M., Hesselman, M. C., te Beek, T. A., van Passel, M. W. J. & Eyre-Walker, A. Rates of lateral gene transfer in prokaryotes: high but why? Trends Microbiol. 23, 598–605 (2015).
Hall, J. P. J., Williams, D., Paterson, S., Harrison, E. & Brockhurst, M. A. Positive selection inhibits gene mobilization and transfer in soil bacterial communities. Nat. Ecol. Evol. 1, 1348–1353 (2017). An elegant study that highlights the role of HGT in general and transposons in particular in the evolution of bacterial soil communities.
Bethke, J. H. et al. Environmental and genetic determinants of plasmid mobility in pathogenic Escherichia coli. Sci. Adv. 6, (2020).
Sørensen, S. J., Bailey, M., Hansen, L. H., Kroer, N. & Wuertz, S. Studying plasmid horizontal transfer in situ: a critical review. Nat. Rev. Microbiol. 3, 700–710 (2005).
Leon-Sampedro, R. et al. Dissemination routes of the carbapenem resistance plasmid pOXA-48 in a hospital setting. Preprint at bioRxiv https://doi.org/10.1101/2020.04.20.050476 (2020).
Gumpert, H. et al. Transfer and persistence of a multi-drug resistance plasmid in situ of the infant gut microbiota in the absence of antibiotic treatment. Front. Microbiol. 8, 1852 (2017).
Porse, A. et al. Genome dynamics of Escherichia coli during antibiotic treatment: transfer, loss, and persistence of genetic elements in situ of the infant gut. Front. Cell. Infect. Microbiol. 7, 126 (2017).
Munck, C., Sheth, R. U., Freedberg, D. E. & Wang, H. H. Recording mobile DNA in the gut microbiota using an Escherichia coli CRISPR-Cas spacer acquisition platform. Nat. Commun. 11, 1–11 (2020).
Thomas, C. M. & Summers, D. Bacterial plasmids. Encycl. Life Sci. https://doi.org/10.1002/9780470015902.a0000468.pub2 (2008).
Summers, D. K. Plasmid replication and its control. in The Biology of Plasmids 31–64 (Blackwell Publishing Ltd., 2009).
Wong, Ng,J., Chatenay, D., Robert, J. & Poirier, M. G. Plasmid copy number noise in monoclonal populations of bacteria. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 81, 011909 (2010).
Münch, K., Münch, R., Biedendieck, R., Jahn, D. & Müller, J. Evolutionary model for the unequal segregation of high copy plasmids. PLoS Comput. Biol. 15, e1006724 (2019).
Nordström, K. Plasmid R1-replication and its control. Plasmid 55, 1–26 (2006).
Jahn, M., Vorpahl, C., Hübschmann, T., Harms, H. & Müller, S. Copy number variability of expression plasmids determined by cell sorting and Droplet Digital PCR. Microb. Cell Fact. 15, 211 (2016).
Mei, H. et al. A high-resolution view of adaptive event dynamics in a plasmid. Genome Biol. Evol. 11, 3022–3034 (2019).
San Millan, A., Escudero, J. A., Gifford, D. R., Mazel, D. & MacLean, R. C. Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria. Nat. Ecol. Evol. 1, 0010 (2016). The first article to show that plasmids increase evolvability of antibiotic resistance.
Santos-Lopez, A. et al. A naturally occurring SNP in plasmid pB1000 produces a reversible increase in antibiotic resistance. Antimicrob. Agents Chemother. 2, AAC.01735-16 (2016).
San Millan, A. et al. Small-plasmid-mediated antibiotic resistance is enhanced by increases in plasmid copy number and bacterial fitness. Antimicrob. Agents Chemother. 59, 3335–3341 (2015).
Thompson, M. G. et al. Isolation and characterization of novel mutations in the pSC101 origin that increase copy number. Sci. Rep. 8, 1590 (2018).
Cho, H. & Winans, S. C. VirA and VirG activate the Ti plasmid repABC operon, elevating plasmid copy number in response to wound-released chemical signals. Proc. Natl Acad. Sci. USA 102, 14843–14848 (2005).
Wang, H. et al. Increased plasmid copy number is essential for Yersinia T3SS function and virulence. Science 353, 492–495 (2016).
Akasaka, N. et al. Change in the plasmid copy number in acetic acid bacteria in response to growth phase and acetic acid concentration. J. Biosci. Bioeng. 119, 661–668 (2015).
Sano, E., Maisnier-Patin, S., Aboubechara, J. P., Quiñones-Soto, S. & Roth, J. R. Plasmid copy number underlies adaptive mutability in bacteria. Genetics 198, 919–933 (2014).
Pappas, K. M. & Winans, S. C. A LuxR-type regulator from Agrobacterium tumefaciens elevates Ti plasmid copy number by activating transcription of plasmid replication genes. Mol. Microbiol. 48, 1059–1073 (2003).
Pecoraro, V., Zerulla, K., Lange, C. & Soppa, J. Quantification of ploidy in proteobacteria revealed the existence of monoploid, (mero-)oligoploid and polyploid species. PLoS ONE 6, e16392 (2011).
Klumpp, S. Growth-rate dependence reveals design principles of plasmid copy number control. PLoS ONE 6, e20403 (2011).
Atlung, T., Christensen, B. B. & Hansen, F. G. Role of the rom protein in copy number control of plasmid pBR322 at different growth rates in Escherichia coli K-12. Plasmid 41, 110–119 (1999).
San Millan, A. et al. Integrative analysis of fitness and metabolic effects of plasmids in Pseudomonas aeruginosa PAO1. ISME J. 12, 3014–3024 (2018).
Park, C. & Zhang, J. High expression hampers horizontal gene transfer. in Genome Biol. Evol. 4, 523–532 (2012).
Condon, C., Liveris, D., Squires, C., Schwartz, I. & Squires, C. L. rRNA operon multiplicity in Escherichia coli and the physiological implications of rrn inactivation. J. Bacteriol. 177, 4152–4156 (1995).
Ikeda, S. et al. Community shifts of soybean stem-associated bacteria responding to different nodulation phenotypes and N levels. ISME J. 4, 315–326 (2010).
Shen, Z. et al. Increased plasmid copy number contributes to the elevated carbapenem resistance in OXA-232-producing Klebsiella pneumoniae. Microb. Drug Resist. https://doi.org/10.1089/mdr.2018.0407 (2019).
El-Halfawy, O. M. & Valvano, M. A. Antimicrobial heteroresistance: an emerging field in need of clarity. Clin. Microbiol. Rev. 28, 191–207 (2015).
Andersson, D. I., Nicoloff, H. & Hjort, K. Mechanisms and clinical relevance of bacterial heteroresistance. Nat. Rev. Microbiol. 17, 479–496 (2019).
Nicoloff, H., Hjort, K., Levin, B. R. & Andersson, D. I. The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification. Nat. Microbiol. 4, 504–514 (2019).
Cascales, E. et al. Colicin biology. Microbiol. Mol. Biol. Rev. 71, 158–229 (2007).
Bayramoglu, B. et al. Bet-hedging in bacteriocin producing Escherichia coli populations: the single cell perspective. Sci. Rep. 7, 42068 (2017).
Mrak, P., Podlesek, Z., Van Putten, J. P. M. & Žgur-Bertok, D. Heterogeneity in expression of the Escherichia coli colicin K activity gene cka is controlled by the SOS system and stochastic factors. Mol. Genet. Genomics 277, 391–401 (2007).
Tomanek, I. et al. Gene amplification as a form of population-level gene expression regulation. Nat. Ecol. Evol. 4, 612–625 (2020).
Rodríguez-Beltrán, J. et al. High recombinant frequency in extraintestinal pathogenic Escherichia coli strains. Mol. Biol. Evol. 32, 1708–1716 (2015).
Niaudet, B., Jannière, L. & Ehrlich, S. D. Recombination between repeated DNA sequences occurs more often in plasmids than in the chromosome of Bacillus subtilis. MGG Mol. Gen. Genet. 197, 46–54 (1984).
Couce, A., Rodríguez-Rojas, A. & Blázquez, J. Bypass of genetic constraints during mutator evolution to antibiotic resistance. Proc. R. Soc. B Biol. Sci. 282, 20142698 (2015).
De Visser, J. A. G. M., Zeyl, C. W., Gerrish, P. J., Blanchard, J. L. & Lenski, R. E. Diminishing returns from mutation supply rate in asexual populations. Science 283, 404–406 (1999).
Million-Weaver, S., Alexander, D. L., Allen, J. M. & Camps, M. Quantifying plasmid copy number to investigate plasmid dosage effects associated with directed protein evolution. Methods Mol. Biol. 834, 33–48 (2012).
Pesesky, M. W., Tilley, R. & Beck, D. A. C. Mosaic plasmids are abundant and unevenly distributed across prokaryotic taxa. Plasmid 102, 10–18 (2019).
Lanza, V. F., Tedim, A. P., Martínez, J. L., Baquero, F. & Coque, T. M. The Plasmidome of Firmicutes: impact on the emergence and the spread of resistance to antimicrobials. Microbiol. Spectr. 3, PLAS-0039-2014 (2015).
Bernheim, A. & Sorek, R. The pan-immune system of bacteria: antiviral defence as a community resource. Nat. Rev. Microbiol. 18, 113–119 (2020).
Roy, D., Huguet, K. T., Grenier, F. & Burrus, V. IncC conjugative plasmids and SXT/R391 elements repair double-strand breaks caused by CRISPR–Cas during conjugation. Nucleic Acids Res. https://doi.org/10.1093/nar/gkaa518 (2020).
Barlow, M., Fatollahi, J. & Salverda, M. Evidence for recombination among the alleles encoding TEM and SHV β-lactamases. J. Antimicrob. Chemother. 63, 256–259 (2009).
Mroczkowska, J. E. & Barlow, M. Recombination and selection can remove blaTEM alleles from bacterial populations. Antimicrob. Agents Chemother. 52, 3408–3410 (2008).
Baquirin, M. H. C. & Barlow, M. Evolution and recombination of the plasmidic qnr alleles. J. Mol. Evol. 67, 103–110 (2008).
Xie, M., Li, R., Liu, Z., Chan, E. W. C. & Chen, S. Recombination of plasmids in a carbapenem-resistant NDM-5-producing clinical Escherichia coli isolate. J. Antimicrob. Chemother. 73, 1230–1234 (2018).
He, D. et al. Emergence of a hybrid plasmid derived from IncN1-F33:A-:B- and mcr-1-bearing plasmids mediated by IS26. J. Antimicrob. Chemother. 74, 3184–3189 (2019).
Li, Y. et al. Evidence of illegitimate recombination between two pasteurellaceae plasmids resulting in a novel multi-resistance replicon, pM3362MDR, in Actinobacillus pleuropneumoniae. Front. Microbiol. 9, 2489 (2018).
Desmet, S. et al. Antibiotic resistance plasmids cointegrated into a megaplasmid harboring the bla OXA-427 carbapenemase gene. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01448-17 (2018).
Fidelma Boyd, E., Hill, C. W., Rich, S. M. & Hard, D. L. Mosaic structure of plasmids from natural populations of Escherichia coli. Genetics 143, 1091–1100 (1996).
Norberg, P., Bergström, M., Jethava, V., Dubhashi, D. & Hermansson, M. The IncP-1 plasmid backbone adapts to different host bacterial species and evolves through homologous recombination. Nat. Commun. 2, 1–11 (2011).
Fernández-López, R. et al. Dynamics of the IncW genetic backbone imply general trends in conjugative plasmid evolution. FEMS Microbiol. Rev. 30, 942–966 (2006).
Osborn, A. M., da Silva Tatley, F. M., Steyn, L. M., Pickup, R. W. & Saunders, J. R. Mosaic plasmids and mosaic replicons: Evolutionary lessons from the analysis of genetic diversity in IncFII-related replicons. Microbiology 146, 2267–2275 (2000).
Gordon, J. E. & Christie, P. J. The Agrobacterium Ti plasmids. Microbiol. Spectr. 2, PLAS-0010-2013 (2014).
Weisberg, A. J. et al. Unexpected conservation and global transmission of agrobacterial virulence plasmids. Science 368, eaba5256 (2020).
Kuzminov, A. Single-strand interruptions in replicating chromosomes cause double-strand breaks. Proc. Natl Acad. Sci. USA 98, 8241–8246 (2001).
Zhang, X., Deatherage, D. E., Zheng, H., Georgoulis, S. J. & Barrick, J. E. Evolution of satellite plasmids can prolong the maintenance of newly acquired accessory genes in bacteria. Nat. Commun. 10, 1–12 (2019). An elegant study highlighting the role of recombination in plasmid evolution.
Bedhomme, S., Perez Pantoja, D. & Bravo, I. G. Plasmid and clonal interference during post horizontal gene transfer evolution. Mol. Ecol. 26, 1832–1847 (2017). A study describing for the first time the effects of plasmid interference in evolving bacterial populations.
Porse, A., Schønning, K., Munck, C. & Sommer, M. O. A. Survival and evolution of a large multidrug resistance plasmid in new clinical bacterial hosts. Mol. Biol. Evol. 33, 2860–2873 (2016).
Novick, R. P. Plasmid incompatibility. Microbiol. Rev. 51, 381–395 (1987).
Ilhan, J. et al. Segregational drift and the interplay between plasmid copy number and evolvability. Mol. Biol. Evol. 36, 472–486 (2019). A study exploring the role of segregational drift in plasmid evolution through a combined experimental and modelling approach.
Szczepanowski, R. et al. Sequencing and comparative analysis of IncP-1α antibiotic resistance plasmids reveal a highly conserved backbone and differences within accessory regions. J. Biotechnol. 155, 95–103 (2011).
Halleran, A. D., Flores-Bautista, E. & Murray, R. M. Quantitative characterization of random partitioning in the evolution of plasmid-encoded traits. Preprint at bioRxiv https://doi.org/10.1101/594879 (2019).
Santer, M. & Uecker, H. Evolutionary rescue and drug resistance on multicopy plasmids. Genetics https://doi.org/10.1534/genetics.119.303012 (2020).
Soskine, M. & Tawfik, D. S. Mutational effects and the evolution of new protein functions. Nat. Rev. Genet. 11, 572–582 (2010).
Barrett, R. D. H. & Schluter, D. Adaptation from standing genetic variation. Trends Ecol. Evol. 23, 38–44 (2008).
Mroczkowska, J. E. & Barlow, M. Fitness trade-offs in blaTEM evolution. Antimicrob. Agents Chemother. 52, 2340–2345 (2008).
Rodriguez-Beltran, J. et al. Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation. Nat. Ecol. Evol. 2, 873–881 (2018). A study exploring the role of plasmids as drivers of evolutionary innovation, highlighting their ability to maintain genetic diversity against strong selective forces.
Doublet, V., Souty-Grosset, C., Bouchon, D., Cordaux, R. & Marcadé, I. A thirty million year-old inherited heteroplasmy. PLoS ONE 3, e2938 (2008).
Haldane, J. B. S. A mathematical theory of natural and artificial selection, part V: selection and mutation. Math. Proc. Camb. Philos. Soc. 23, 838–844 (1927).
Sun, L. et al. Effective polyploidy causes phenotypic delay and influences bacterial evolvability. PLoS Biol. 16, e2004644 (2018).
Rodríguez-Beltrán, J. et al. Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2001240117 (2020). The first article to demonstrate that genetic dominance shapes plasmid evolution and genetic content.
Zheng, J. et al. Plasmids are vectors for redundant chromosomal genes in the Bacillus cereus group. BMC Genomics 16, 6 (2015).
Sheppard, A. E. et al. Nested Russian doll-like genetic mobility drives rapid dissemination of the carbapenem resistance gene blakpc. Antimicrob. Agents Chemother. 60, 3767–3778 (2016).
Dimitriu, T., Marchant, L., Buckling, A. & Raymond, B. Bacteria from natural populations transfer plasmids mostly towards their kin. Proc. R. Soc. B Biol. Sci. 286, 20191110 (2019).
Baharoglu, Z., Bikard, D. & Mazel, D. Conjugative DNA transfer induces the bacterial SOS response and promotes antibiotic resistance development through integron activation. PLoS Genet. 6, e1001165 (2010). A study that elegantly demonstrates that the SOS system is induced in response to plasmid conjugative transfer and how this leads to genomic rearrangements.
Maslowska, K. H., Makiela-Dzbenska, K. & Fijalkowska, I. J. The SOS system: a complex and tightly regulated response to DNA damage. Environ. Mol. Mutagen. 60, 368–384 (2019).
Howarth, S. Resistance to the bactericidal effect of ultraviolet radiation conferred on Enterobacteria by the colicine factor coli. J. Gen. Microbiol. 40, 43–55 (1965).
Strike, P. & Lodwick, D. Plasmid genes affecting DNA repair and mutation. J. Cell Sci. 1987 (Suppl. 6), 303–321 (1987).
Woodgate, R. & Sedgwick, S. G. Mutagenesis induced by bacterial UmuDC proteins and their plasmid homologues. Mol. Microbiol. 6, 2213–2218 (1992).
Remigi, P. et al. Transient hypermutagenesis accelerates the evolution of legume endosymbionts following horizontal gene transfer. PLoS Biol. 12, e1001942 (2014).
Nguyen, A., Maisnier-Patin, S., Yamayoshi, I., Kofoid, E. & Roth, J. R. Selective inbreeding: genetic crosses drive apparent adaptive mutation in the cairns-foster system of Escherichia coli. Genetics 214, 333–354 (2020).
Silva, R. F. et al. Pervasive sign epistasis between conjugative plasmids and drug-resistance chromosomal mutations. PLoS Genet. 7, e1002181 (2011).
Loftie-Eaton, W. et al. Evolutionary paths that expand plasmid host-range: implications for spread of antibiotic resistance. Mol. Biol. Evol. 33, 885–897 (2016).
Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010).
Cooper, V. S., Vohr, S. H., Wrocklage, S. C. & Hatcher, P. J. Why genes evolve faster on secondary chromosomes in bacteria. PLoS Comput. Biol. 6, e1000732 (2010).
Eberhard, W. G. Evolution in bacterial plasmids and levels of selection. Q. Rev. Biol. 65, 3–22 (1990).
Hug, L. A. et al. A new view of the tree of life. Nat. Microbiol. 1, 1–6 (2016).
Galata, V., Fehlmann, T., Backes, C. & Keller, A. PLSDB: a resource of complete bacterial plasmids. Nucleic Acids Res. 47, D195–D202 (2019).
San Millan, A. & MacLean, R. C. Fitness costs of plasmids: a limit to plasmid transmission. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.MTBP-0016-2017 (2017).
Vogwill, T. & Maclean, R. C. The genetic basis of the fitness costs of antimicrobial resistance: a meta-analysis approach. Evol. Appl. 8, 284–295 (2015).
Salje, J. Plasmid segregation: how to survive as an extra piece of DNA. Crit. Rev. Biochem. Mol. Biol. 45, 296–317 (2010).
Harrison, E. & Brockhurst, M. A. Plasmid-mediated horizontal gene transfer is a coevolutionary process. Trends Microbiol. 20, 262–267 (2012).
Stewart, F. M. & Levin, B. R. The population biology of bacterial plasmids: a priori conditions for the existence of conjugationally transmitted factors. Genetics 87, (1977).
San Millan, A., Heilbron, K. & MacLean, R. C. Positive epistasis between co-infecting plasmids promotes plasmid survival in bacterial populations. ISME J. 8, 601–612 (2014).
Bouma, J. E. & Lenski, R. E. Evolution of a bacteria/plasmid association. Nature 335, 351–352 (1988). The first demonstration of compensatory evolution in a bacterial–plasmid association.
Harrison, E., Guymer, D., Spiers, A. J., Paterson, S. & Brockhurst, M. A. Parallel compensatory evolution stabilizes plasmids across the parasitism-mutualism continuum. Curr. Biol. 25, 2034–2039 (2015).
Wein, T., Hülter, N. F., Mizrahi, I. & Dagan, T. Emergence of plasmid stability under non-selective conditions maintains antibiotic resistance. Nat. Commun. 10, 1–13 (2019).
San Millan, A. et al. Positive selection and compensatory adaptation interact to stabilize non-transmissible plasmids. Nat. Commun. 5, 5208 (2014).
Bottery, M. J., Wood, A. J. & Brockhurst, M. A. Adaptive modulation of antibiotic resistance through intragenomic coevolution. Nat. Ecol. Evol. 1, 1364–1369 (2017).
Li, L. et al. Plasmids persist in a microbial community by providing fitness benefit to multiple phylotypes. ISME J. 14, 1170–1181 (2020).
Alonso-del Valle, A. et al. The distribution of plasmid fitness effects explains plasmid persistence in bacterial. Preprint at bioRxiv https://doi.org/10.1101/2020.08.01.230672 (2020).
Jordt, H. et al. Coevolution of host–plasmid pairs facilitates the emergence of novel multidrug resistance. Nat. Ecol. Evol. https://doi.org/10.1038/s41559-020-1170-1 (2020).
Hall, J. P. J., Wood, A. J., Harrison, E. & Brockhurst, M. A. Source-sink plasmid transfer dynamics maintain gene mobility in soil bacterial communities. Proc. Natl Acad. Sci. USA 113, 8260–8265 (2016).
Stalder, T. et al. Evolving populations in biofilms contain more persistent plasmids. Mol. Biol. Evol. 37, 1563–1576 (2020).
Ridenhour, B. J. et al. Persistence of antibiotic resistance plasmids in bacterial biofilms. Evol. Appl. 10, 640–647 (2017).
Lopatkin, A. J. et al. Persistence and reversal of plasmid-mediated antibiotic resistance. Nat. Commun. 8, 1689 (2017).
Taddei, F. et al. Role of mutator alleles in adaptive evolution. Nature 387, 700–702 (1997).
San Millan, A. Evolution of plasmid-mediated antibiotic resistance in the clinical context. Trends Microbiol. 26, 978–985 (2018).
Arredondo-Alonso, S. et al. Plasmids shaped the recent emergence of the major nosocomial pathogen Enterococcus faecium. mBio 11, (2020).
Ramsay, J. P. & Firth, N. Diverse mobilization strategies facilitate transfer of non-conjugative mobile genetic elements. Curr. Opin. Microbiol. 38, 1–9 (2017).
Barry, K. E. et al. Don’t overlook the little guy: an evaluation of the frequency of small plasmids co-conjugating with larger carbapenemase gene containing plasmids. Plasmid 103, 1–8 (2019).
Peña-Miller, R., Rodríguez-González, R., Maclean, R. C. & San Millan, A. Evaluating the effect of horizontal transmission on the stability of plasmids under different selection regimes. Mob. Genet. Elem. 5, 29–33 (2015).
Clark, A. J. & Warren, G. J. Conjugal transmission of plasmids. Annu. Rev. Genet. 13, 99–125 (1979).
Chen, J. et al. Genome hypermobility by lateral transduction. Science 362, 207–212 (2018).
Halary, S., Leigh, J. W., Cheaib, B., Lopez, P. & Bapteste, E. Network analyses structure genetic diversity in independent genetic worlds. Proc. Natl Acad. Sci. USA 107, 127–132 (2010).
Erdmann, S., Tschitschko, B., Zhong, L., Raftery, M. J. & Cavicchioli, R. A plasmid from an Antarctic haloarchaeon uses specialized membrane vesicles to disseminate and infect plasmid-free cells. Nat. Microbiol. 2, 1446–1455 (2017).
Abe, K., Nomura, N. & Suzuki, S. Biofilms: Hot spots of horizontal gene transfer (HGT) in aquatic environments, with a focus on a new HGT mechanism. FEMS Microbiol. Ecol. https://doi.org/10.1093/femsec/fiaa031 (2020).
Dubey, G. P. & Ben-Yehuda, S. Intercellular nanotubes mediate bacterial communication. Cell 144, 590–600 (2011).
Porse, A., Schou, T. S., Munck, C., Ellabaan, M. M. H. & Sommer, M. O. A. Biochemical mechanisms determine the functional compatibility of heterologous genes. Nat. Commun. 9, 522 (2018).
Sánchez-Osuna, M., Cortés, P., Barbé, J. & Erill, I. Origin of the mobile di-hydro-pteroate synthase gene determining sulfonamide resistance in clinical isolates. Front. Microbiol. 10, (2019).
Guo, Q. et al. Glutathione-S-transferase FosA6 of Klebsiella pneumoniae origin conferring fosfomycin resistance in ESBL-producing Escherichia coli. J. Antimicrob. Chemother. 71, 2460–2465 (2016).
Kirby, R. Evolutionary origin of the class A and class C β-lactamases. J. Mol. Evol. 34, 345–350 (1992).
Woodford, N. & Ellington, M. J. The emergence of antibiotic resistance by mutation. Clin. Microbiol. Infect. 13, 5–18 (2007).
This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC grant agreement 757440-PLASREVOLUTION) and by the Instituto de Salud Carlos III (grant PI16-00860) co-funded by European Regional Development Fund “A way to achieve Europe”. Á.S.M. is supported by a Miguel Servet Fellowship (MS15-00012). J.R.-B. is a recipient of a Juan de la Cierva-Incorporación Fellowship (IJC2018-035146-I) co-funded by Agencia Estatal de Investigación del Ministerio de Ciencia e Innovación. R.C.M. is supported by a Wellcome Trust grant (106918/Z/15/Z). Á.S.M, J.R.-B. and R.L.-S. are members of the Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP).
The authors declare no competing interests.
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- Horizontal gene transfer
(HGT). Transfer of genetic material between cells that do not share an ancestor–descendant relationship.
- Postsegregational killing systems
Genetic systems that ensure plasmid maintenance. They typically rely on the production of a long-lasting toxin and a short-lived antitoxin. If the plasmid is lost in a daughter cell, the antitoxin is rapidly degraded and the stable toxin kills the plasmid-free cell.
- Compensatory evolution
Process by which the fitness cost produced by the acquisition of a plasmid is ameliorated through mutations in the chromosome and/or the plasmid.
- Second-order selection
Process by which evolution, while directly selecting for adaptive genetic variability, indirectly selects for the system that created that variability.
- Type IV CRISPR–Cas systems
Recently characterized CRISPR–Cas systems found predominantly on plasmids and that primarily target other plasmids. Type IV CRISPR–Cas systems are thus believed to have a role in mediating interplasmid competition.
- Plasmid segregation
Physical separation of plasmid molecules to be inherited by daughter cells during cell division.
- Gene dosage effects
Effect by which the phenotype of a given mutation is proportional to the cumulative number of mutant alleles present in the cell.
- Tandem genetic duplications
Duplication of a region of DNA adjacent to the original one.
Stochastic process by which some individuals in a community are better suited to tackle environmental perturbations, usually at the price of a reduced growth rate in the short term.
Exchange of genetic information between two distinct DNA molecules.
- Mutator strains
Strains that permanently show unusually high mutation rates due to a malfunction of a DNA repair mechanism.
- Transposable elements
DNA sequences that can move within genomes by a cut-and-paste mechanism.
Coexistence of two different plasmids sharing the same nucleotide sequences for all regions involved in the replication and maintenance system within the same cell. Cells carrying plasmids under heteroplasmy are dubbed ‘heteroplasmid cells’, whereas cells carrying a unique version of a plasmid are termed ‘homoplasmid cells’.
- Genetic drift
Change in allele frequency in a population due to random sampling.
- Clonal interference
Competition between cellular lineages in a population arising from different beneficial mutations in asexually reproducing organisms.
- Standing genetic variation
The presence of more than one allele at a locus in a population before environmental change.
In evolution, trade-offs are negative correlations between ancestral and novel traits.
- SOS stress response
Coordinated cellular response to genotoxic stress that involves the expression of more than 40 genes whose main function is to repair damaged DNA.
Genetic element composed by an integrase gene and a recombination site in which gene cassettes can be directionally integrated or excised by integrase-mediated site-specific recombination.
- Epistatic interactions
Phenomenon by which the phenotypic contribution of a gene varies depending on the presence or absence of another gene. The phenotypic effect of both genes in combination is thus different from the effect expected according to the phenotypes they conferred separately.
- Purifying selection
Selective pressure that eliminates deleterious alleles from populations.
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Cite this article
Rodríguez-Beltrán, J., DelaFuente, J., León-Sampedro, R. et al. Beyond horizontal gene transfer: the role of plasmids in bacterial evolution. Nat Rev Microbiol 19, 347–359 (2021). https://doi.org/10.1038/s41579-020-00497-1
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