This article is about the DNA molecule. For the physics phenomenon, seeplasmoid.
Diagram of a bacterium showing chromosomal DNA and plasmids (Not to scale)
Aplasmid is a small,extrachromosomal DNA molecule within a cell that is physically separated fromchromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules inbacteria; however, plasmids are sometimes present inarchaea andeukaryotic organisms.[1][page needed][2] Plasmids often carry useful genes, such as those involved inantibiotic resistance,virulence,[3][4][5]secondary metabolism[6] andbioremediation.[7][8] While chromosomes are large and contain all the essential genetic information for living under normal conditions, plasmids are usually very small and contain additional genes for special circumstances.
Artificial plasmids are widely used asvectors inmolecular cloning, serving to drive the replication ofrecombinant DNA sequences within host organisms. In the laboratory, plasmids may be introduced into a cell viatransformation. Synthetic plasmids are available for procurement over the internet by various vendors using submitted sequences typically designed with software, if a design does not work the vendor may make additional edits from the submission.[9][10][11]
Plasmids are consideredreplicons, units of DNA capable of replicating autonomously within a suitable host. However, plasmids, likeviruses, are not generally classified aslife.[12] Plasmids are transmitted from one bacterium to another (even of another species) mostly throughconjugation.[3] This host-to-host transfer of genetic material is one mechanism ofhorizontal gene transfer, and plasmids are considered part of themobilome. Unlike viruses, which encase their genetic material in a protective protein coat called acapsid, plasmids are "naked" DNA and do not encode genes necessary to encase the genetic material for transfer to a new host; however, some classes of plasmids encode theconjugative "sex" pilus necessary for their own transfer. Plasmids vary in size from 1 to over 400 kbp,[13] and the number of identical plasmids in a singlecell can range from one up to thousands.
The termplasmid was coined in 1952 by the Americanmolecular biologistJoshua Lederberg to refer to "any extrachromosomal hereditary determinant."[14][15] The term's early usage included any bacterial genetic material that exists extrachromosomally for at least part of its replication cycle, but because that description includes bacterial viruses, the notion of plasmid was refined over time to refer to genetic elements that reproduce autonomously.[16]Later in 1968, it was decided that the term plasmid should be adopted as the term for extrachromosomal genetic element,[17] and to distinguish it from viruses, the definition was narrowed to genetic elements that exist exclusively or predominantly outside of the chromosome, can replicate autonomously, and contribute to transferring mobile elements between unrelated bacteria.[3][4][16]
There are two types of plasmid integration into a host bacteria: Non-integrating plasmids replicate as with the top instance, whereasepisomes, the lower example, can integrate into the hostchromosome.
In order for plasmids to replicate independently within a cell, they must possess a stretch of DNA that can act as anorigin of replication. The self-replicating unit, in this case, the plasmid, is called areplicon. A typical bacterial replicon may consist of a number of elements, such as the gene for plasmid-specific replication initiation protein (Rep), repeating units callediterons,DnaA boxes, and an adjacent AT-rich region.[16] Smaller plasmids make use of the host replicative enzymes to make copies of themselves, while larger plasmids may carry genes specific for the replication of those plasmids. A few types of plasmids can also insert into the host chromosome, and these integrative plasmids are sometimes referred to asepisomes inprokaryotes.[18]
Plasmids almost always carry at least one gene. Many of the genes carried by a plasmid are beneficial for the host cells, for example: enabling the host cell to survive in an environment that would otherwise be lethal or restrictive for growth. Some of these genes encode traits for antibiotic resistance or resistance to heavy metal, while others may producevirulence factors that enable a bacterium to colonize a host and overcome its defences or have specific metabolic functions that allow the bacterium to utilize a particular nutrient, including the ability to degrade recalcitrant or toxic organic compounds.[19] Plasmids can also provide bacteria with the ability tofix nitrogen. Some plasmids, calledcryptic plasmids, don't appear to provide any clear advantage to its host, yet still persist in bacterial populations.[20] However, recent studies show that they may play a role in antibiotic resistance by contributing to heteroresistance within bacterial populations.[21]
Naturally occurring plasmids vary greatly in their physical properties. Their size can range from very small mini-plasmids of less than 1-kilobase pairs (kbp) to very large megaplasmids of several megabase pairs (Mbp). At the upper end, little differs between a megaplasmid and aminichromosome. Plasmids are generally circular, but examples of linear plasmids are also known. These linear plasmids require specialized mechanisms to replicate their ends.[16]
Plasmids may be present in an individual cell in varying number, ranging from one to several hundreds. The normal number of copies of plasmid that may be found in a single cell is called theplasmid copy number, and is determined by how the replication initiation is regulated and the size of the molecule. Larger plasmids tend to have lower copy numbers.[18] Low-copy-number plasmids that exist only as one or a few copies in each bacterium are, uponcell division, in danger of being lost in one of the segregating bacteria. Such single-copy plasmids have systems that attempt to actively distribute a copy to both daughter cells. These systems, which include theparABS system andparMRC system, are often referred to as thepartition system or partition function of a plasmid.[22]
Overview of bacterial conjugationElectron micrograph of a DNA fiber bundle, presumably of a single bacterial chromosome loopElectron micrograph of a bacterial DNA plasmid (chromosome fragment)
Plasmids may be classified in a number of ways. Plasmids can be broadly classified into conjugative plasmids and non-conjugative plasmids. Conjugative plasmids contain a set oftransfer genes which promote sexual conjugation between different cells.[18] In the complex process ofconjugation, plasmids may be transferred from one bacterium to another viasex pili encoded by some of the transfer genes (see figure).[24] Non-conjugative plasmids are incapable of initiating conjugation, hence they can be transferred only with the assistance of conjugative plasmids. An intermediate class of plasmids are mobilizable, and carry only a subset of the genes required for transfer. They can parasitize a conjugative plasmid, transferring at high frequency only in its presence.[25]
Plasmids can also be classified into incompatibility groups. A microbe can harbour different types of plasmids, but different plasmids can only exist in a single bacterial cell if they are compatible. If two plasmids are not compatible, one or the other will be rapidly lost from the cell. Different plasmids may therefore be assigned to different incompatibility groups depending on whether they can coexist together. Incompatible plasmids (belonging to the same incompatibility group) normally share the same replication or partition mechanisms and can thus not be kept together in a single cell.[26][27] Incompatibility typing (or Inc typing) was traditionally achieved by genetic phenotyping methods, testing whether cells stably transmit plasmid pairs to their progeny.[28] This has largely been superseded by genetic methods such as PCR, and more recently by whole-genome sequencing methods with bioinformatic tools such as PlasmidFinder.[29]
Another way to classify plasmids is by function. There are five main classes:
FertilityF-plasmids, which containtra genes. They are capable ofconjugation and result in the expression ofsex pili.[15][30] F-plasmids are categorized as either (+) or (-) and contribute to the difference of being a donor or recipient during conjugation.[15][30][31]
Resistance (R) plasmids, which contain genes that provide resistance againstantibiotics or antibacterial agents was first discovered in 1959.[32] R-factors where seen as the contributing factor for the spread ofmultidrug resistance in bacteria, some R-plasmids assist in transmissibility of other specifically non- self transmissible R-factors.[33][34] Historically known as R-factors, before the nature of plasmids was understood.
Col plasmids, which contain genes that code forbacteriocins,proteins that can kill other bacteria.
Degradative plasmids, which enable the digestion of unusual substances, e.g.toluene andsalicylic acid.
Virulence plasmids, which turn the bacterium into apathogen. e.g.Ti plasmid inAgrobacterium tumefaciens. Bacteria under selective pressure will keep plasmids containing virulence factors as it is a cost - benefit for survival, removal of the selective pressure can lead to the loss of a plasmid due to the expenditure of energy needed to keep it is no longer justified.[5][35]
Plasmids can belong to more than one of these functional groups.
With the wider availability of whole genome sequencing which is able to capture the genetic sequence of plasmids, methods have been developed to cluster or type plasmids based on their sequence content. Plasmid multi-locus sequence typing (pMLST) is based on chromosomalMultilocus sequence typing by matching the sequence of replication machinery genes to databases of previously classified sequences. If the sequenceallele matches the database, this is used as the plasmid classification, and therefore has higher sensitivity than a simple presence or absence test of these genes.[29]
A related method is to useaverage nucleotide identity between plasmids to find close genetic neighbours. Tools which use this approach include COPLA[36] and MOB-cluster.[37]
Creating typing classifications usingunsupervised learning, that is without a pre-existing database or 'reference-free', has been shown to be useful in grouping plasmids in new datasets without biasing or being limited to representations in a pre-built database—tools to do this include mge-cluster.[38] As plasmid frequently change their gene content and order, modelling genetic distances between them using methods designed for point mutations can lead to poor estimates of the true evolutionary distance between plasmids. Tools such as pling find homologous sequence regions between plasmids, and more accurately reconstruct the number of evolutionary events (structural variants) between each pair, then use unsupervised clustering apporaches to group plasmids.[39]
Although most plasmids are double-stranded DNA molecules, some consist ofsingle-stranded DNA, or predominantlydouble-stranded RNA. RNA plasmids are non-infectious extrachromosomal linear RNA replicons, bothencapsidated and unencapsidated, which have been found in fungi and various plants, from algae to land plants. In many cases, however, it may be difficult or impossible to clearly distinguish RNA plasmids from RNA viruses and other infectious RNAs.[40]
Chromids are elements that exist at the boundary between achromosome and a plasmid, found in about 10% of bacterial species sequenced by 2009. These elements carry core genes and havecodon usage similar to the chromosome, yet use a plasmid-type replication mechanism such as the low copy number RepABC. As a result, they have been variously classified as minichromosomes or megaplasmids in the past.[41] InVibrio, the bacterium synchronizes the replication of the chromosome and chromid by a conserved genome size ratio.[42]
Artificially constructed plasmids may be used asvectors ingenetic engineering. These plasmids serve as important tools in genetics and biotechnology labs, where they are commonly used to clone and amplify (make many copies of) orexpress particular genes.[43] A wide variety of plasmids are commercially available for such uses. The gene to be replicated is normally inserted into a plasmid that typically contains a number of features for their use. These include a gene that confers resistance to particular antibiotics (ampicillin is most frequently used for bacterial strains), anorigin of replication to allow the bacterial cells to replicate the plasmid DNA, and a suitable site for cloning (referred to as amultiple cloning site).
DNA structural instability can be defined as a series of spontaneous events that culminate in an unforeseen rearrangement, loss, or gain of genetic material. Such events are frequently triggered by the transposition of mobile elements or by the presence of unstable elements such as non-canonical (non-B) structures. Accessory regions pertaining to the bacterial backbone may engage in a wide range of structural instability phenomena. Well-known catalysts ofgenetic instability include direct, inverted, and tandem repeats, which are known to be conspicuous in a large number of commercially available cloning and expression vectors.[44] Insertion sequences can also severely impact plasmid function and yield, by leading todeletions and rearrangements, activation,down-regulation or inactivation of neighboringgene expression.[45] Therefore, the reduction or complete elimination of extraneousnoncoding backbone sequences would pointedly reduce the propensity for such events to take place, and consequently, the overall recombinogenic potential of the plasmid.[46][47]
A schematic representation of thepBR322 plasmid, one of the first plasmids to be used widely as acloning vector. Shown on the plasmid diagram are the genes encoded (amp andtet forampicillin andtetracycline resistance respectively), its origin of replication (ori), and variousrestriction sites (indicated in blue).
Plasmids are the most-commonly used bacterial cloning vectors.[48] These cloning vectors contain a site that allows DNA fragments to be inserted, for example amultiple cloning site or polylinker which has several commonly usedrestriction sites to which DNA fragments may beligated. After the gene of interest is inserted, the plasmids are introduced into bacteria by a process calledtransformation. These plasmids contain aselectable marker, usually an antibiotic resistance gene, which confers on the bacteria an ability to survive and proliferate in a selective growth medium containing the particular antibiotics. The cells after transformation are exposed to the selective media, and only cells containing the plasmid may survive. In this way, the antibiotics act as a filter to select only the bacteria containing the plasmid DNA. The vector may also contain othermarker genes orreporter genes to facilitate selection of plasmids with cloned inserts. Bacteria containing the plasmid can then be grown in large amounts, harvested, and the plasmid of interest may then be isolated using various methods ofplasmid preparation.
Suicide vectors are plasmids that are unable to replicate in the host cell and therefore have to integrate in the chromosome or disappear.[50] One example of these vectors are pMQ30 plasmid. This plasmid has SacB gene fromBacillus subtilis which can be induced by sucrose and it'll be lethal when expressed in Gram-negative bacteria.[51] The benefit of this system( two-step success monitoring ) shows when the experiment design needs a target gene to be integrated into the chromosome of the bacterial host. In the first step after transforming the host cells with the plasmid, a media with specific antibiotic could be used to select for bacteria that contain the plasmid. The second step makes sure that only the bacteria with integrated plasmid would survive. Since the plasmid contain the SacB gene that will induce toxicity in presence of sucrose, only the bacteria would survive and grow that has the plasmid integrated in their chromosome.
Another major use of plasmids is to make large amounts of proteins. In this case, researchers grow bacteria containing a plasmid harboring the gene of interest. Just as the bacterium produces proteins to confer its antibiotic resistance, it can also be induced to produce large amounts of proteins from the inserted gene. This is a cheap and easy way of mass-producing the protein, for example, utilizing the rapid reproduction of E.coli with a plasmid containing theinsulin gene leads to a large production of insulin.[52][53][54]
Plasmids may also be used for gene transfer as a potential treatment ingene therapy so that it may express the protein that is lacking in the cells. Some forms ofgene therapy require the insertion of therapeuticgenes at pre-selectedchromosomal target sites within the humangenome. Plasmid vectors are one of many approaches that could be used for this purpose.Zinc finger nucleases (ZFNs) offer a way to cause a site-specificdouble-strand break to the DNA genome and causehomologous recombination. Plasmids encoding ZFN could help deliver a therapeutic gene to a specific site so thatcell damage, cancer-causing mutations, or animmune response is avoided.[55]
Plasmids were historically used to genetically engineer the embryonic stem cells of rats to create rat genetic disease models. The limited efficiency of plasmid-based techniques precluded their use in the creation of more accurate human cell models. However, developments inadeno-associated virus recombination techniques, andzinc finger nucleases, have enabled the creation of a new generation ofisogenic human disease models.
Plasmids assist in transportingbiosynthetic gene clusters - a set of gene that contain all the necessary enzymes that lead to the production of special metabolites (formally known assecondary metabolite).[56] A benefit of using plasmids to transfer BGC is demonstrated by using a suitable host that can mass produce specialized metabolites, some of these molecules are able to control microbial population.[57][58] Plasmids can contain and express several BGCs with a few plasmids known to be exclusive for transferring BGCs.[58] BGC's can also be transfers to the host organism's chromosome, utilizing a plasmid vector, which allows for studies in gene knockout experiments.[59] By using plasmids for the uptake of BGCs, microorganisms can gain an advantage as production is not limited to antibiotic resistant biosynthesis genes but the production oftoxins/antitoxins.[60]
The termepisome was introduced byFrançois Jacob andÉlie Wollman in 1958 to refer to extra-chromosomal genetic material that may replicate autonomously or become integrated into the chromosome.[61][62] Since the term was introduced, however, its use has changed, asplasmid has become the preferred term for autonomously replicating extrachromosomal DNA. At a 1968 symposium in London some participants suggested that the termepisome be abandoned, although others continued to use the term with a shift in meaning.[63][64]
Today, some authors useepisome in the context of prokaryotes to refer to a plasmid that is capable of integrating into the chromosome. The integrative plasmids may be replicated and stably maintained in a cell through multiple generations, but at some stage, they will exist as an independent plasmid molecule.[65] In the context of eukaryotes, the termepisome is used to mean a non-integrated extrachromosomal closed circular DNA molecule that may be replicated in the nucleus.[66][67] Viruses are the most common examples of this, such asherpesviruses,adenoviruses, andpolyomaviruses, but some are plasmids. Other examples include aberrant chromosomal fragments, such asdouble minute chromosomes, that can arise during artificial gene amplifications or in pathologic processes (e.g., cancer cell transformation). Episomes in eukaryotes behave similarly to plasmids in prokaryotes in that the DNA is stably maintained and replicated with the host cell. Cytoplasmic viral episomes (as inpoxvirus infections) can also occur. Some episomes, such as herpesviruses, replicate in arolling circle mechanism, similar tobacteriophages (bacterial phage viruses). Others replicate through a bidirectional replication mechanism (Theta type plasmids). In either case, episomes remain physically separate from host cell chromosomes. Several cancer viruses, includingEpstein-Barr virus andKaposi's sarcoma-associated herpesvirus, are maintained as latent, chromosomally distinct episomes in cancer cells, where the viruses expressoncogenes that promote cancer cell proliferation. In cancers, these episomes passively replicate together with host chromosomes when the cell divides. When these viral episomes initiatelytic replication to generate multiple virus particles, they generally activate cellularinnate immunity defense mechanisms that kill the host cell.
Some plasmids or microbial hosts include anaddiction system or postsegregational killing system (PSK), such as thehok/sok (host killing/suppressor of killing) system of plasmid R1 inEscherichia coli.[68] This variant produces both a long-livedpoison and a short-livedantidote. Several types of plasmid addiction systems (toxin/ antitoxin, metabolism-based, ORT systems) were described in theliterature[69] and used in biotechnical (fermentation) or biomedical (vaccine therapy) applications. Daughter cells that retain a copy of the plasmid survive, while a daughter cell that fails to inherit the plasmid dies or suffers a reduced growth-rate because of the lingering poison from the parent cell. Finally, the overall productivity could be enhanced.[clarification needed]
In contrast, plasmids used in biotechnology, such as pUC18, pBR322 and derived vectors, hardly ever contain toxin-antitoxin addiction systems, and therefore need to be kept under antibiotic pressure to avoid plasmid loss.
Other types of plasmids are often related to yeast cloning vectors that include:
Yeast integrative plasmid (YIp), yeast vectors that rely on integration into the host chromosome for survival and replication, and are usually used when studying the functionality of a solo gene or when the gene is toxic. Also connected with the gene URA3, that codes an enzyme related to the biosynthesis of pyrimidine nucleotides (T, C);
Yeast Replicative Plasmid (YRp), which transport a sequence of chromosomal DNA that includes an origin of replication. These plasmids are less stable, as they can be lost during budding.
The mitochondria of many higher plants containself-replicating, extra-chromosomal linear or circular DNA molecules which have been considered to be plasmids. These can range from 0.7 kb to 20 kb in size. The plasmids have been generally classified into two categories- circular and linear.[71] Circular plasmids have been isolated and found in many different plants, with those inVicia faba andChenopodium album being the most studied and whose mechanism of replication is known. The circular plasmids can replicate using the θ model of replication (as inVicia faba) and throughrolling circle replication (as inC.album).[72] Linear plasmids have been identified in some plant species such asBeta vulgaris,Brassica napus,Zea mays, etc. but are rarer than their circular counterparts.
The function and origin of these plasmids remains largely unknown. It has been suggested that the circular plasmids share a common ancestor, some genes in the mitochondrial plasmid have counterparts in the nuclear DNA suggesting inter-compartment exchange. Meanwhile, the linear plasmids share structural similarities such as invertrons with viral DNA and fungal plasmids, like fungal plasmids they also have low GC content, these observations have led to some hypothesizing that these linear plasmids have viral origins, or have ended up in plant mitochondria throughhorizontal gene transfer from pathogenic fungi.[71][73]
Plasmids are often used to purify a specific sequence, since they can easily be purified away from the rest of the genome. For their use as vectors, and formolecular cloning, plasmids often need to be isolated.
There are several methods toisolate plasmid DNA from bacteria, ranging from the plasmid extraction kits (miniprep to the maxiprep or bulkprep),alkaline lysis, enzymatic lysis, and mechanical lysis .[43] The former can be used to quickly find out whether the plasmid is correct in any of several bacterial clones. The yield is a small amount of impure plasmid DNA, which is sufficient for analysis byrestriction digest and for some cloning techniques.
In the latter, much larger volumes of bacterial suspension are grown from which a maxi-prep can be performed. In essence, this is a scaled-up miniprep followed by additional purification. This results in relatively large amounts (several hundred micrograms) of very pure plasmid DNA.
Many commercial kits have been created to perform plasmid extraction at various scales, purity, and levels of automation.
Plasmid DNA may appear in one of five conformations, which (for a given size) run at different speeds in a gel duringelectrophoresis. The conformations are listed below in order of electrophoretic mobility (speed for a given applied voltage) from slowest to fastest:
Relaxed circular DNA is fully intact with both strands uncut but has been enzymaticallyrelaxed (supercoils removed). This can be modeled by letting a twisted extension cord unwind and relax and then plugging it into itself.
Linear DNA has free ends, either because both strands have been cut or because the DNA was linearin vivo. This can be modeled with an electrical extension cord that is not plugged into itself.
Supercoiled (orcovalently closed-circular) DNA is fully intact with both strands uncut, and with an integral twist, resulting in a compact form. This can be modeled by twisting anextension cord and then plugging it into itself.
Supercoileddenatured DNA is similar tosupercoiled DNA, but has unpaired regions that make it slightly less compact; this can result from excessive alkalinity during plasmid preparation.
The rate of migration for small linear fragments is directly proportional to the voltage applied at low voltages. At higher voltages, larger fragments migrate at continuously increasing yet different rates. Thus, the resolution of a gel decreases with increased voltage.
At a specified, low voltage, the migration rate of small linear DNA fragments is a function of their length. Large linear fragments (over 20 kb or so) migrate at a certain fixed rate regardless of length. This is because the molecules 'respirate', with the bulk of the molecule following the leading end through the gel matrix.Restriction digests are frequently used to analyse purified plasmids. These enzymes specifically break the DNA at certain short sequences. The resulting linear fragments form 'bands' aftergel electrophoresis. It is possible to purify certain fragments by cutting the bands out of the gel and dissolving the gel to release the DNA fragments.
Because of its tight conformation, supercoiled DNA migrates faster through a gel than linear or open-circular DNA.
The use of plasmids as a technique inmolecular biology is supported bybioinformaticssoftware. These programs record theDNA sequence of plasmid vectors, help to predict cut sites ofrestriction enzymes, and to plan manipulations. Examples of software packages that handle plasmid maps are ApE,Clone Manager, GeneConstructionKit, Geneious,Genome Compiler, LabGenius, Lasergene,MacVector, pDraw32, Serial Cloner,UGENE, VectorFriends,Vector NTI, and WebDSV. These pieces of software help conduct entire experiments in silico before doing wet experiments.[74]
Many plasmids have been created over the years and researchers have given out plasmids to plasmid databases such as the non-profit organisationsAddgene andBCCM/GeneCorner. One can find and request plasmids from those databases for research.Researchers also often upload plasmid sequences to theNCBI database, from which sequences of specific plasmids can be retrieved. There have been multiple efforts to create curated and quality controlled databases from these uploaded sequences; an early example is by Orleket al,[75] which limited itself toEnterobacteriaceae plasmids, while COMPASS also encompassed plasmids from other bacteria. More recently, PLSDB[76] was made as a more up to date curated database of NCBI plasmids, and as of 2024 contains over 72,000 entries.[77] A similar database is pATLAS, which additionally includes visual analytics tools to show relationships between plasmids.[78] The largest plasmid database made from publicly available data is IMG/PR, which not only contains full plasmid sequences retrieved from NCBI, but novel plasmid genomes found frommetagenomes and metatranscriptomes.[79]
Other datasets have been created by sequencing and computing plasmid genomes from pre-existing bacterial collections, e.g. the NORM collection[80][81] and the Murray Collection.[82][83]
^Esser K, Kück U, Lang-Hinrichs C, Lemke P, Osiewacz HD, Stahl U, et al. (1986).Plasmids of Eukaryotes: fundamentals and Applications. Berlin: Springer-Verlag.ISBN978-3-540-15798-4.
^Wickner RB, Hinnebusch A, Lambowitz AM, Gunsalus IC, Hollaender A, eds. (1987). "Mitochondrial and Chloroplast Plasmids".Extrachromosomal Elements in Lower Eukaryotes. Boston, MA: Springer US. pp. 81–146.ISBN978-1-4684-5251-8.
^abCarattoli A (August 2013). "Plasmids and the spread of resistance".International Journal of Medical Microbiology. Special Issue Antibiotic Resistance.303 (6–7):298–304.doi:10.1016/j.ijmm.2013.02.001.PMID23499304.
^Bhatt P, Bhandari G, Bhatt K, Maithani D, Mishra S, Gangola S, et al. (October 2021). "Plasmid-mediated catabolism for the removal of xenobiotics from the environment".Journal of Hazardous Materials.420: 126618.Bibcode:2021JHzM..42026618B.doi:10.1016/j.jhazmat.2021.126618.PMID34329102.
^Sinkovics J, Horvath J, Horak A (1998). "The origin and evolution of viruses (a review)".Acta Microbiologica et Immunologica Hungarica.45 (3–4):349–390.PMID9873943.
^Udo E, Jacob L (January 1998). "Conjugative Transfer of High-Level Mupirocin Resistance and the Mobilization of Non-Conjugative Plasmids in Staphylococcus aureus".Microbial Drug Resistance.4 (3):185–193.doi:10.1089/mdr.1998.4.185.PMID9818970.
^Datta N (1977). "Classification of plasmids as an aid to understanding their epidemiology and evolution".Journal of Antimicrobial Chemotherapy.3 (suppl C):19–23.doi:10.1093/jac/3.suppl_c.19.PMID599130.
^Harrison PW, Lower RP, Kim NK, Young JP (April 2010). "Introducing the bacterial 'chromid': not a chromosome, not a plasmid".Trends in Microbiology.18 (4):141–148.doi:10.1016/j.tim.2009.12.010.PMID20080407.
^Gonçalves GA, Oliveira PH, Gomes AG, Prather KL, Lewis LA, Prazeres DM, et al. (August 2014). "Evidence that the insertion events of IS2 transposition are biased towards abrupt compositional shifts in target DNA and modulated by a diverse set of culture parameters".Applied Microbiology and Biotechnology.98 (15):6609–6619.doi:10.1007/s00253-014-5695-6.hdl:1721.1/104375.PMID24769900.S2CID9826684.
^Oliveira PH, Mairhofer J (September 2013). "Marker-free plasmids for biotechnological applications - implications and perspectives".Trends in Biotechnology.31 (9):539–547.doi:10.1016/j.tibtech.2013.06.001.PMID23830144.
^Oliveira PH, Prather KJ, Prazeres DM, Monteiro GA (September 2009). "Structural instability of plasmid biopharmaceuticals: challenges and implications".Trends in Biotechnology.27 (9):503–511.doi:10.1016/j.tibtech.2009.06.004.PMID19656584.
^Heidorn T, Camsund D, Huang HH, Lindberg P, Oliveira P, Stensjö K, et al. (2011). "Synthetic Biology in Cyanobacteria".Synthetic Biology, Part A. Methods in Enzymology. Vol. 497. pp. 539–579.doi:10.1016/B978-0-12-385075-1.00024-X.ISBN978-0-12-385075-1.PMID21601103.Integrative plasmids are in most cases suicide vectors, that is, vectors that are unable to replicate in the destination host and therefore must either integrate or disappear, and hence, any plasmid that can be efficiently transferred into the recipient may be used.
^Quandt J, Hynes MF (May 1993). "Versatile suicide vectors which allow direct selection for gene replacement in Gram-negative bacteria".Gene.127 (1):15–21.doi:10.1016/0378-1119(93)90611-6.PMID8486283.
^Kandavelou K, Chandrasegaran S (2008). "Plasmids for Gene Therapy".Plasmids: Current Research and Future Trends. Caister Academic Press.ISBN978-1-904455-35-6.
^Hemmerling F, Piel J (May 2022). "Strategies to access biosynthetic novelty in bacterial genomes for drug discovery".Nature Reviews. Drug Discovery.21 (5):359–378.doi:10.1038/s41573-022-00414-6.PMID35296832.
^Davies J (July 2013). "Specialized microbial metabolites: functions and origins".The Journal of Antibiotics.66 (7):361–364.doi:10.1038/ja.2013.61.PMID23756686.
^Jacob F, Wollman EL (1958), "Les épisomes, elements génétiques ajoutés",Comptes Rendus de l'Académie des Sciences de Paris,247 (1):154–56,PMID13561654
^Handa H (January 2008). "Linear plasmids in plant mitochondria: peaceful coexistences or malicious invasions?".Mitochondrion.8 (1):15–25.doi:10.1016/j.mito.2007.10.002.PMID18326073.
^Cazares A, Figueroa W, Cazares D, Lima L, Turnbull JD, McGregor H, et al. (2024). Pre and Post antibiotic epoch: Insights into the historical spread of antimicrobial resistance (Preprint).doi:10.1101/2024.09.03.610986.
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