View source for Plasmid

{{Short description|Small DNA molecule within a cell}}
{{about|the DNA molecule|the physics phenomenon|plasmoid}}
{{Use dmy dates|date=November 2022}}
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[[File:plasmid (english).svg|thumb|upright=1.35|Diagram of a bacterium showing chromosomal DNA and plasmids (Not to scale)]]
A '''plasmid''' is a small, [[extrachromosomal DNA]] molecule within a cell that is physically separated from [[gDNA|chromosomal DNA]] and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in [[bacteria]]<ref name="MicrobioJ">{{cite journal | vauthors = Lloyd GS, Thomas CM | title = Microbial Primer: The logic of bacterial plasmids | journal = Microbiology  | volume = 169 | issue = 7 | page = 001336| date = July 2023  | pmid = 37395112 | pmc = 10433415 | doi = 10.1099/mic.0.001336 | doi-access = free }}</ref>  and [[archaea]];<ref name="pmid25694123">{{cite journal |last1=Wang |first1=H |last2=Peng |first2=N |last3=Shah |first3=SA |last4=Huang |first4=L |last5=She |first5=Q |title=Archaeal extrachromosomal genetic elements. |journal=Microbiology and Molecular Biology Reviews |date=March 2015 |volume=79 |issue=1 |pages=117–52 |doi=10.1128/MMBR.00042-14 |pmid=25694123|pmc=4402960 }}</ref> however plasmids are sometimes present in [[eukaryote|eukaryotic organisms]] as well.<ref>{{cite book |vauthors=Esser K, Kück U, Lang-Hinrichs C, Lemke P, Osiewacz HD, Stahl U, Tudzynski P |title=Plasmids of Eukaryotes: fundamentals and Applications |date=1986 |publisher=Springer-Verlag |location=Berlin |isbn=978-3-540-15798-4}}</ref>{{page needed|date=December 2024}}<ref name=Wickner87>{{cite book  |chapter=Mitochondrial and Chloroplast Plasmids |pages=81–146 |veditors=Wickner RB, Hinnebusch A, Lambowitz AM, Gunsalus IC, Hollaender A  |title=Extrachromosomal Elements in Lower Eukaryotes |date=1987 |publisher=Springer US |location=Boston, MA |isbn=978-1-4684-5251-8 }}</ref> Plasmids often carry useful genes, such as those involved in [[antibiotic resistance]], [[virulence]],<ref name="Smillie_2010">{{cite journal |vauthors=Smillie C, Garcillán-Barcia MP, Francia MV, Rocha EP, de la Cruz F |title=Mobility of plasmids |journal=Microbiology and Molecular Biology Reviews |volume=74 |issue=3 |pages=434–452 |date=September 2010 |pmid=20805406 |pmc=2937521 |doi=10.1128/MMBR.00020-10 }}</ref><ref name="Carattoli_2013">{{cite journal |vauthors=Carattoli A |title=Plasmids and the spread of resistance |journal=International Journal of Medical Microbiology |volume=303 |issue=6–7 |pages=298–304 |date=August 2013 |pmid=23499304 |doi=10.1016/j.ijmm.2013.02.001 |series=Special Issue Antibiotic Resistance }}</ref><ref name=":1">{{Cite journal |last1=San Millan |first1=Alvaro |last2=MacLean |first2=R. Craig |date=2017-09-22 |editor-last=Baquero |editor-first=Fernando |editor2-last=Bouza |editor2-first=Emilio |editor3-last=Gutiérrez-Fuentes |editor3-first=J.A. |editor4-last=Coque |editor4-first=Teresa M. |title=Fitness Costs of Plasmids: a Limit to Plasmid Transmission |journal=Microbiology Spectrum |volume=5 |issue=5 |doi=10.1128/microbiolspec.MTBP-0016-2017 |pmid=28944751 |pmc=11687550 }}</ref> [[secondary metabolism]]<ref>{{cite journal |last1=Saati-Santamaría |first1=Zaki |title=Global Map of Specialized Metabolites Encoded in Prokaryotic Plasmids |journal=Microbiology Spectrum |date=17 August 2023 |volume=11 |issue=4 |pages=e0152323 |doi=10.1128/spectrum.01523-23 |pmid=37310275 |pmc=10434180 }}</ref> and [[bioremediation]].<ref>{{cite journal |last1=Bhatt |first1=Pankaj |last2=Bhandari |first2=Geeta |last3=Bhatt |first3=Kalpana |last4=Maithani |first4=Damini |last5=Mishra |first5=Sandhya |last6=Gangola |first6=Saurabh |last7=Bhatt |first7=Rakesh |last8=Huang |first8=Yaohua |last9=Chen |first9=Shaohua |title=Plasmid-mediated catabolism for the removal of xenobiotics from the environment |journal=Journal of Hazardous Materials |date=October 2021 |volume=420 |article-number=126618 |doi=10.1016/j.jhazmat.2021.126618 |pmid=34329102 |bibcode=2021JHzM..42026618B }}</ref><ref>{{cite journal |last1=Saati-Santamaría |first1=Zaki |last2=Navarro-Gómez |first2=Pilar |last3=Martínez-Mancebo |first3=Juan A |last4=Juárez-Mugarza |first4=Maitane |last5=Flores |first5=Amando |last6=Canosa |first6=Inés |title=Genetic and species rearrangements in microbial consortia impact biodegradation potential |journal=The ISME Journal |date=25 January 2025 |volume=19 |doi=10.1093/ismejo/wraf014 |pmid=39861970 |pmc=11892951 }}</ref> 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 as [[Vector (molecular biology)|vectors]] in [[molecular cloning]], serving to drive the replication of [[recombinant DNA]] sequences within host organisms. In the laboratory, plasmids may be introduced into a cell via [[transformation (genetics)|transformation]]. 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.<ref>{{Cite web |url=https://www.genscript.com/synthetic-biology-gene-synthesis-service.html |title=GenBrick Gene Synthesis - Long DNA Sequences &#124; GenScript}}</ref><ref>{{Cite web |url=https://www.idtdna.com/pages/products/genes-and-gene-fragments/custom-gene-synthesis |title=Gene synthesis &#124; IDT |website=Integrated DNA Technologies}}</ref><ref>{{cite web |url=https://www.thermofisher.com/se/en/home/life-science/cloning/gene-synthesis/geneart-gene-synthesis.html |title=Invitrogen GeneArt Gene Synthesis}}</ref>

Plasmids are considered ''[[replicon (genetics)|replicon]]s'', units of DNA capable of replicating autonomously within a suitable host. However, plasmids, like [[virus]]es, are not generally classified as [[life]].<ref>{{cite journal |vauthors=Sinkovics J, Horvath J, Horak A |title=The origin and evolution of viruses (a review) |journal=Acta Microbiologica et Immunologica Hungarica |volume=45 |issue=3–4 |pages=349–390 |year=1998 |pmid=9873943 }}</ref> Plasmids are transmitted from one bacterium to another (even of another species) mostly through [[Bacterial conjugation|conjugation]].<ref name="Smillie_2010" /> This host-to-host transfer of genetic material is one mechanism of [[horizontal gene transfer]], and plasmids are considered part of the [[mobilome]]. Unlike viruses, which encase their genetic material in a protective protein coat called a [[capsid]], 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 the [[pilus#Conjugative pili|conjugative "sex" pilus]] necessary for their own transfer. Plasmids vary in size from 1 to over 400 k[[base pair|bp]],<ref name="ThomasSummers2008">{{cite encyclopedia |vauthors=Thomas CM, Summers D |chapter=Bacterial Plasmids |year=2008|doi=10.1002/9780470015902.a0000468.pub2 |encyclopedia=Encyclopedia of Life Sciences |isbn=978-0-470-01617-6 }}</ref> and the number of identical plasmids in a single [[cell (biology)|cell]] can range from one up to thousands.

==History==

The term ''plasmid'' was coined in 1952 by the American [[molecular biology|molecular biologist]] [[Joshua Lederberg]] to refer to "any extrachromosomal hereditary determinant."<ref>{{cite journal | vauthors = Lederberg J | title = Cell genetics and hereditary symbiosis | journal = Physiological Reviews | volume = 32 | issue = 4 | pages = 403–430 | date = October 1952 | pmid = 13003535 | doi = 10.1152/physrev.1952.32.4.403 | citeseerx = 10.1.1.458.985 }}</ref><ref name="Helinski_2022">{{cite journal | vauthors = Helinski DR | title = A Brief History of Plasmids | journal = EcoSal Plus | volume = 10 | issue = 1 | pages = eESP00282021 | date = December 2022 | pmid = 35373578 | pmc = 10729939 | doi = 10.1128/ecosalplus.ESP-0028-2021 | veditors = Kaper JB }}</ref> 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.<ref name=Hayes_2003 />
Later in 1968, it was decided that the term plasmid should be adopted as the term for extrachromosomal genetic element,<ref>{{cite web |url=http://mgen.microbiologyresearch.org/about/content/journal/mgen/standing-on-the-shoulders-of-giants/falkow3 |title=Microbial Genomics: Standing on the Shoulders of Giants | vauthors = Falkow S |work=Microbiology Society}}</ref> 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.<ref name="Smillie_2010" /><ref name="Carattoli_2013" /><ref name=Hayes_2003 />

==Properties and characteristics==
[[File:Plasmid replication (english).svg|400px|thumb|right|There are two types of plasmid integration into a host bacteria: Non-integrating plasmids replicate as with the top instance, whereas [[episomes]], the lower example, can integrate into the host [[chromosome]].]]

In order for plasmids to replicate independently within a cell, they must possess a stretch of DNA that can act as an [[origin of replication]].  The self-replicating unit, in this case, the plasmid, is called a [[Replicon (genetics)|replicon]].  A typical bacterial replicon may consist of a number of elements, such as the gene for plasmid-specific replication initiation protein (Rep), repeating units called [[iteron]]s, [[DnaA]] boxes, and an adjacent AT-rich region.<ref name=Hayes_2003/> 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 as [[episome]]s in [[prokaryote]]s.<ref name="brown">{{cite book |chapter-url= https://books.google.com/books?id=yEvt3JdtgTQC&pg=PT26 |title= Gene Cloning and DNA Analysis: An Introduction| vauthors = Brown TA |publisher= Wiley-Blackwell |edition= 6th |year= 2010 |chapter= Chapter 2 – Vectors for Gene Cloning: Plasmids and Bacteriophages |isbn= 978-1-4051-8173-0}}</ref>

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 produce [[virulence factor]]s 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.<ref>{{cite journal | vauthors = Smyth C, Leigh RJ, Delaney S, Murphy RA, Walsh F | title = Shooting hoops: globetrotting plasmids spreading more than just antimicrobial resistance genes across One Health | journal = Microbial Genomics | volume = 8 | issue = 8 | pages = 1–10 | date = August 2022 | pmid = 35960657 | pmc = 9484753 | doi = 10.1099/mgen.0.000858 | doi-access = free }}</ref> Plasmids can also provide bacteria with the ability to [[nitrogen fixation|fix nitrogen]]. Some plasmids, called [[cryptic plasmids]], don't appear to provide any clear advantage to its host, yet still persist in bacterial populations.<ref>{{Cite journal |last1=Fogarty |first1=Emily C. |last2=Schechter |first2=Matthew S. |last3=Lolans |first3=Karen |last4=Sheahan |first4=Madeline L. |last5=Veseli |first5=Iva |last6=Moore |first6=Ryan M. |last7=Kiefl |first7=Evan |last8=Moody |first8=Thomas |last9=Rice |first9=Phoebe A. |last10=Yu |first10=Michael K. |last11=Mimee |first11=Mark |last12=Chang |first12=Eugene B. |last13=Ruscheweyh |first13=Hans-Joachim |last14=Sunagawa |first14=Shinichi |last15=Mclellan |first15=Sandra L. |date=February 2024 |title=A cryptic plasmid is among the most numerous genetic elements in the human gut |journal=Cell |language=en |volume=187 |issue=5 |pages=1206–1222.e16 |doi=10.1016/j.cell.2024.01.039 |pmc=10973873 |pmid=38428395}}</ref> However, recent studies show that they may play a role in antibiotic resistance by contributing to heteroresistance within bacterial populations.<ref>{{cite journal | vauthors = Nicoloff H, Hjort K, Andersson DI, Wang H | title = Three concurrent mechanisms generate gene copy number variation and transient antibiotic heteroresistance | journal = Nature Communications | volume = 15 | issue = 1 | article-number = 3981 | date = May 2024 | pmid = 38730266 | pmc = 11087502 | doi = 10.1038/s41467-024-48233-0 | bibcode = 2024NatCo..15.3981N }}</ref>

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 a [[minichromosome]].  Plasmids are generally circular, but examples of linear plasmids are also known.  These linear plasmids require specialized mechanisms to replicate their ends.<ref name=Hayes_2003>{{cite book | vauthors = Hayes F |chapter= Chapter 1 – The Function and Organization of Plasmids |chapter-url= https://books.google.com/books?id=r6QC0hTwsrwC&pg=PA2 | veditors = Casali N, Presto A |title= E. Coli Plasmid Vectors: Methods and Applications  |series= Methods in Molecular Biology |volume=235|publisher= Humana Press |year= 2003  |pages= 1–5 |isbn= 978-1-58829-151-6}}</ref>

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 the [[plasmid 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.<ref name="brown"/> Low-copy-number plasmids that exist only as one or a few copies in each bacterium are, upon [[cell 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 the [[parABS system]] and [[parMRC system]], are often referred to as the [[Plasmid partition system|partition system]] or partition function of a plasmid.<ref>{{cite journal | vauthors = Dmowski M, Jagura-Burdzy G | title = Active stable maintenance functions in low copy-number plasmids of Gram-positive bacteria I. Partition systems | journal = Polish Journal of Microbiology | volume = 62 | issue = 1 | pages = 3–16 | date = 2013 | pmid = 23829072 | doi = 10.33073/pjm-2013-001 | doi-access = free }}</ref>
{{Further|Regulatory region of repBA gene}}

Plasmids of ''linear'' form are unknown among [[phytopathogen]]s with one exception, ''[[Rhodococcus fascians]]''.<ref name = "Coup-d-Etat" >{{cite journal | vauthors = Stes E, Vandeputte OM, El Jaziri M, Holsters M, Vereecke D | title = A successful bacterial coup d'état: how Rhodococcus fascians redirects plant development | journal = Annual Review of Phytopathology | volume = 49 | issue = 1 | pages = 69–86 | date = 2011 | pmid = 21495844 | doi = 10.1146/annurev-phyto-072910-095217 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | bibcode = 2011AnRvP..49...69S }}</ref>

==Classifications and types==
[[File:Conjugation.svg|right|250px|thumb|Overview of bacterial conjugation]]
[[File:DNA Under electron microscope Image 3576B-PH.jpg|thumb|[[Electron micrograph]] of a DNA fiber bundle, presumably of a single bacterial chromosome loop]]
[[File:Plasmid em-en.jpg|thumb|Electron 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 of [[transfer gene]]s which promote sexual conjugation between different cells.<ref name="brown"/> In the complex process of [[Bacterial conjugation|conjugation]], plasmids may be transferred from one bacterium to another via [[Pilus#Conjugative pili|sex pili]] encoded by some of the transfer genes (see figure).<ref>{{cite book |url=https://books.google.com/books?id=Mhs-P94d1R8C&pg=PA795 |title=Molecular Biology | vauthors = Clark DP, Pazdernik NJ |page=795 |edition=2nd |publisher=Academic Cell |year= 2012 |isbn=978-0-12-378594-7 }}</ref> 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.<ref>{{cite journal |last1=Udo |first1=E.E. |last2=Jacob |first2=L.E. |title=Conjugative Transfer of High-Level Mupirocin Resistance and the Mobilization of Non-Conjugative Plasmids in Staphylococcus aureus |journal=Microbial Drug Resistance |date=January 1998 |volume=4 |issue=3 |pages=185–193 |doi=10.1089/mdr.1998.4.185 |pmid=9818970 }}</ref>

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.<ref>{{cite book | vauthors = Radnedge L, Richards H | chapter = Chapter 2: The Development of Plasmid Vectors. | chapter-url=https://books.google.com/books?id=w0jvDl0zJPIC&pg=PA76 | date = January 1999 | volume = 29 | pages = 51–96 (75–77) | veditors = Smith MC, Sockett RE |title=Genetic Methods for Diverse Prokaryotes |series=Methods in Microbiology |publisher= Academic Press |isbn= 978-0-12-652340-9 }}</ref><ref>{{cite web|url=http://blog.addgene.org/plasmid-101-origin-of-replication|title=Plasmids 101: Origin of Replication |website=addgene.org}}</ref> Incompatibility typing (or Inc typing) was traditionally achieved by genetic phenotyping methods, testing whether cells stably transmit plasmid pairs to their progeny.<ref name="Johnson_2009">{{cite book | vauthors = Johnson TJ, Nolan LK | title = Plasmid replicon typing | series = Methods in Molecular Biology (Clifton, N.J.) | volume = 551 | pages = 27–35 | date = 2009 }}</ref> 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.<ref name="Carattoli_2014">{{cite journal | vauthors = Carattoli A, Zankari E, García-Fernández A, Voldby Larsen M, Lund O, Villa L, Møller Aarestrup F, Hasman H | title = In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 7 | pages = 3895–3903 | date = 2014 | doi = 10.1128/AAC.02412-14 | pmid = 24777092 | pmc = 4068535 }}</ref>

Another way to classify plasmids is by function. There are five main classes:
* Fertility [[F-plasmid]]s, which contain ''tra'' genes. They are capable of [[bacterial conjugation|conjugation]] and result in the expression of [[Pilus#Conjugative pili|sex pili]].<ref name="Helinski_2022" /><ref name=":0">{{cite journal | vauthors = Watanabe T, Nishida H, Ogata C, Arai T, Sato S | title = EPISOME-MEDIATED TRANSFER OF DRUG RESISTANCE IN ENTEROBACTERIACEAE. VII. TWO TYPES OF NATURALLY OCCURRING R FACTORS | journal = Journal of Bacteriology | volume = 88 | issue = 3 | pages = 716–726 | date = September 1964 | pmid = 14208512 | pmc = 277371 | doi = 10.1128/jb.88.3.716-726.1964 }}</ref> F-plasmids are categorized as either (+) or (-) and contribute to the difference of being a donor or recipient during conjugation.<ref name="Helinski_2022" /><ref name=":0" /><ref>{{Cite journal |last1=Meynell |first1=Elinor |last2=Datta |first2=Naomi |date=February 1966 |title=The relation of resistance transfer factors to the F-factor (sex-factor) of Escherichia coli K12 |journal=Genetics Research |language=en |volume=7 |issue=1 |pages=134–140 |doi=10.1017/S0016672300009538 |pmid=5324663 |doi-access=free }}</ref>
* Resistance (R) plasmids, which contain genes that provide resistance against [[antibiotic]]s or antibacterial agents was first discovered in 1959.<ref>{{cite journal |last1=Datta |first1=N. |title=Classification of plasmids as an aid to understanding their epidemiology and evolution |journal=Journal of Antimicrobial Chemotherapy |date=1977 |volume=3 |issue=suppl C |pages=19–23 |doi=10.1093/jac/3.suppl_c.19 |pmid=599130 }}</ref> R-factors where seen as the contributing factor for the spread of [[Multiple drug resistance|multidrug resistance]] in bacteria, some R-plasmids assist in transmissibility of other specifically non- self transmissible R-factors.<ref>{{cite journal |last1=Watanabe |first1=Tsutomu |title=Infective Heredity of Multiple Drug Resistance in Bacteria |journal=Bacteriological Reviews |date=1963 |volume=27 |issue=1 |pages=87–115 |doi=10.1128/mmbr.27.1.87-115.1963 |pmid=13999115 |pmc=441171 }}</ref><ref>{{cite journal |last1=Anderson |first1=E. S. |last2=Lewis |first2=M. J. |title=Characterization of a Transfer Factor Associated with Drug Resistance in Salmonella typhimurium |journal=Nature |date=November 1965 |volume=208 |issue=5013 |pages=843–849 |doi=10.1038/208843a0 |pmid=5331112 |bibcode=1965Natur.208..843A }}</ref> Historically known as R-factors, before the nature of plasmids was understood. 
* Col plasmids, which contain genes that code for [[bacteriocin]]s, [[protein]]s that can kill other bacteria.
* Degradative plasmids, which enable the digestion of unusual substances, e.g. [[toluene]] and [[salicylic acid]].
* Virulence plasmids, which turn the bacterium into a [[pathogen]]. e.g. [[Ti plasmid]] in ''[[Agrobacterium 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.<ref name=":1" /><ref>{{cite book |doi=10.1016/b978-0-12-813288-3.00035-5 |chapter=Preface to Third Edition |title=Molecular Biology |date=2019 |last1=Clark |first1=David P. |last2=Pazdernik |first2=Nanette J. |last3=McGehee |first3=Michelle R. |pages=xiii-xiv |isbn=978-0-12-813288-3 }}</ref>

Plasmids can belong to more than one of these functional groups.

===Sequence-based plasmid typing===
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 chromosomal [[Multilocus sequence typing]] by matching the sequence of replication machinery genes to databases of previously classified sequences. If the sequence [[allele]] 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.<ref name="Carattoli_2014" />

A related method is to use [[average nucleotide identity]] between plasmids to find close genetic neighbours. Tools which use this approach include COPLA<ref name="RedondoSalvo_2021">{{cite journal | vauthors = Redondo-Salvo S, Bartomeus-Peñalver R, Vielva L, Tagg KA, Webb HE, Fernández-López R, de la Cruz F | title = COPLA, a taxonomic classifier of plasmids | journal = BMC Bioinformatics | volume = 22 | issue = 1 | article-number = 390 | date = 2021 | doi = 10.1186/s12859-021-04299-x | doi-access = free | pmid = 34332528 | pmc = 8325299 }}</ref> and MOB-cluster.<ref name="Robertson_2018">{{cite journal | vauthors = Robertson J, Nash J | title = MOB-suite: software tools for clustering, reconstruction and typing of plasmids from draft assemblies | journal = Microbial Genomics | volume = 4 | issue = 8 | date = 2018 | doi = 10.1099/mgen.0.000206 | doi-access = free | pmid = 30052170 | pmc = 6159552 }}</ref>

Creating typing classifications using [[unsupervised 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.<ref name="ArredondoAlonso_2023">{{cite journal | vauthors = Arredondo-Alonso S, Gladstone RA, Pöntinen AK, Gama JA, Schürch AC, Lanza VF, Johnsen PJ, Samuelsen Ø, Tonkin-Hill G, Corander J | title = Mge-cluster: a reference-free approach for typing bacterial plasmids | journal = NAR Genomics and Bioinformatics | volume = 5 | issue = 3 | article-number = lqad066 | date = 2023 | doi = 10.1093/nargab/lqad066 | pmid = 37435357 | pmc = 10331934 }}</ref> 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 approaches to group plasmids.<ref name="Frolova_2024">{{cite journal | vauthors = Frolova D, Lima L, Roberts LW, Bohnenkämper L, Wittler R, Stoye J, Iqbal Z | title = Applying rearrangement distances to enable plasmid epidemiology with pling | journal = Microbial Genomics | volume = 10 | issue = 10 | page = 001300 | date = 2024 | doi = 10.1099/mgen.0.001300 | doi-access = free | pmid = 39401066 | pmc = 11472880 }}</ref>

===RNA plasmids===
Although most plasmids are double-stranded DNA molecules, some consist of [[single-stranded DNA]], or predominantly [[double-stranded RNA]]. RNA plasmids are non-infectious extrachromosomal linear RNA replicons, both [[Virus-like particle|encapsidated]] 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.<ref name = "Brown_1989">{{cite book | vauthors = Brown GG, Finnegan PM | title = RNA Plasmids | series = [[International Review of Cytology]] | volume = 117 | pages = 1–56 | date = January 1989 | pmid = 2684889 | doi = 10.1016/s0074-7696(08)61333-9 | isbn = 978-0-12-364517-3 }}</ref>

===Chromids===
{{main|Chromid}}
Chromids are elements that exist at the boundary between a [[chromosome]] and a plasmid, found in about 10% of bacterial species sequenced by 2009. These elements carry core genes and have [[codon 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.<ref>{{cite journal | vauthors = Harrison PW, Lower RP, Kim NK, Young JP | title = Introducing the bacterial 'chromid': not a chromosome, not a plasmid | journal = Trends in Microbiology | volume = 18 | issue = 4 | pages = 141–148 | date = April 2010 | pmid = 20080407 | doi = 10.1016/j.tim.2009.12.010 }}</ref> In ''[[Vibrio]]'', the bacterium synchronizes the replication of the chromosome and chromid by a conserved genome size ratio.<ref name=Bruhn>{{cite journal | vauthors = Bruhn M, Schindler D, Kemter FS, Wiley MR, Chase K, Koroleva GI, Palacios G, Sozhamannan S, Waldminghaus T | title = Functionality of Two Origins of Replication in ''Vibrio cholerae'' Strains With a Single Chromosome | journal = Frontiers in Microbiology | volume = 9 | page = 2932 | date = 30 November 2018 | pmid = 30559732 | pmc = 6284228 | doi = 10.3389/fmicb.2018.02932 | doi-access = free }}</ref>

==Vectors==
{{Further|Vector (molecular biology)}}
Artificially constructed plasmids may be used as [[vector (molecular biology)|vectors]] in [[genetic 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) or [[gene expression|express]] particular genes.<ref name="Molecular cloning">{{cite book | vauthors = Russell DW, Sambrook J |title=Molecular cloning: a laboratory manual |publisher=Cold Spring Harbor Laboratory |location=Cold Spring Harbor, NY |year=2001 }}</ref> 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), an [[origin of replication]] to allow the bacterial cells to replicate the plasmid DNA, and a suitable site for cloning (referred to as a [[multiple 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 of [[genetic instability]] include direct, inverted, and tandem repeats, which are known to be conspicuous in a large number of commercially available cloning and expression vectors.<ref>{{cite journal | vauthors = Oliveira PH, Prather KJ, Prazeres DM, Monteiro GA | title = Analysis of DNA repeats in bacterial plasmids reveals the potential for recurrent instability events | journal = Applied Microbiology and Biotechnology | volume = 87 | issue = 6 | pages = 2157–2167 | date = August 2010 | pmid = 20496146 | doi = 10.1007/s00253-010-2671-7 | s2cid = 19780633 | doi-access = free }}</ref> Insertion sequences can also severely impact plasmid function and yield, by leading to [[deletion (genetics)|deletion]]s and rearrangements, activation, [[down-regulation]] or inactivation of neighboring [[gene expression]].<ref>{{cite journal | vauthors = Gonçalves GA, Oliveira PH, Gomes AG, Prather KL, Lewis LA, Prazeres DM, Monteiro GA | title = 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 | journal = Applied Microbiology and Biotechnology | volume = 98 | issue = 15 | pages = 6609–6619 | date = August 2014 | pmid = 24769900 | doi = 10.1007/s00253-014-5695-6 | hdl-access = free | s2cid = 9826684 | hdl = 1721.1/104375 }}</ref> Therefore, the reduction or complete elimination of extraneous [[noncoding DNA|noncoding]] backbone sequences would pointedly reduce the propensity for such events to take place, and consequently, the overall recombinogenic potential of the plasmid.<ref>{{cite journal | vauthors = Oliveira PH, Mairhofer J | title = Marker-free plasmids for biotechnological applications - implications and perspectives | journal = Trends in Biotechnology | volume = 31 | issue = 9 | pages = 539–547 | date = September 2013 | pmid = 23830144 | doi = 10.1016/j.tibtech.2013.06.001 }}</ref><ref>{{cite journal | vauthors = Oliveira PH, Prather KJ, Prazeres DM, Monteiro GA | title = Structural instability of plasmid biopharmaceuticals: challenges and implications | journal = Trends in Biotechnology | volume = 27 | issue = 9 | pages = 503–511 | date = September 2009 | pmid = 19656584 | doi = 10.1016/j.tibtech.2009.06.004 }}</ref>

[[File:pBR322.svg|thumb|A schematic representation of the [[pBR322]] plasmid, one of the first plasmids to be used widely as a [[cloning vector]].  Shown on the plasmid diagram are the genes encoded (''amp'' and ''tet'' for [[ampicillin]] and [[tetracycline]] resistance respectively), its origin of replication (''ori''), and various [[restriction site]]s (indicated in blue).]]

===Cloning===
{{main|Cloning vector}}
Plasmids are the most-commonly used bacterial cloning vectors.<ref name="uldis">{{cite book | vauthors = Geoghegan T | chapter = Molecular Applications | chapter-url=https://books.google.com/books?id=1wyf7pbR5z4C&pg=PA248 |title=Modern Microbial Genetics | veditors = Streips UN, Yasbin RE |publisher=Wiley-Blackwell |edition= 2nd |year= 2002 |isbn= 978-0-471-38665-0 |page=248 }}</ref> These cloning vectors contain a site that allows DNA fragments to be inserted, for example a [[multiple cloning site]] or polylinker which has several commonly used [[restriction sites]] to which DNA fragments may be [[Ligation (molecular biology)|ligated]]. After the gene of interest is inserted, the plasmids are introduced into bacteria by a process called [[transformation (genetics)|transformation]]. These plasmids contain a [[selectable 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 other [[marker gene]]s or [[reporter gene]]s 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 of [[plasmid preparation]].

A plasmid cloning vector is typically used to clone DNA fragments of up to 15 [[base pair|kbp]].<ref>{{cite book | vauthors = Preston A |chapter=Chapter 2 – Choosing a Cloning Vector |pages=19–26 |chapter-url=https://books.google.com/books?id=r6QC0hTwsrwC&pg=PA19  | veditors = Casali N, Preston A  |title=E. Coli Plasmid Vectors: Methods and Applications|series=Methods in Molecular Biology | volume = 235 |publisher=Humana Press |year= 2003  |isbn=978-1-58829-151-6}}</ref> To clone longer lengths of DNA, [[lambda phage]] with lysogeny genes deleted, [[cosmid]]s, [[bacterial artificial chromosome]]s, or [[yeast artificial chromosome]]s are used.

=== Suicide Vectors (plasmids) ===
Suicide vectors are plasmids that are unable to replicate in the host cell and therefore have to integrate in the chromosome or disappear.<ref>{{cite book |doi=10.1016/B978-0-12-385075-1.00024-X |chapter=Synthetic Biology in Cyanobacteria |title=Synthetic Biology, Part A |series=Methods in Enzymology |date=2011 |last1=Heidorn |first1=Thorsten |last2=Camsund |first2=Daniel |last3=Huang |first3=Hsin-Ho |last4=Lindberg |first4=Pia |last5=Oliveira |first5=Paulo |last6=Stensjö |first6=Karin |last7=Lindblad |first7=Peter |volume=497 |pages=539–579 |pmid=21601103 |isbn=978-0-12-385075-1 |quote=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. }}</ref> One example of these vectors are pMQ30 plasmid. This plasmid has SacB gene from ''Bacillus subtilis'' which can be induced by sucrose and will be lethal when expressed in Gram-negative bacteria.<ref>{{cite journal |last1=Quandt |first1=Jürgen |last2=Hynes |first2=Michael F. |title=Versatile suicide vectors which allow direct selection for gene replacement in Gram-negative bacteria |journal=Gene |date=May 1993 |volume=127 |issue=1 |pages=15–21 |doi=10.1016/0378-1119(93)90611-6 |pmid=8486283 }}</ref> 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.

===Protein Production===
{{main|Expression vector}}
[[File:Human insulin 100IU-ml vial white background.jpg|thumb|Insulin]]
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 the [[insulin]] gene leads to a large production of insulin.<ref>{{Cite journal |last1=Goeddel |first1=D V |last2=Kleid |first2=D G |last3=Bolivar |first3=F |last4=Heyneker |first4=H L |last5=Yansura |first5=D G |last6=Crea |first6=R |last7=Hirose |first7=T |last8=Kraszewski |first8=A |last9=Itakura |first9=K |last10=Riggs |first10=A D |date=January 1979 |title=Expression in Escherichia coli of chemically synthesized genes for human insulin. |journal=Proceedings of the National Academy of Sciences |volume=76 |issue=1 |pages=106–110 |doi=10.1073/pnas.76.1.106 |doi-access=free |pmc=382885 |pmid=85300 |bibcode=1979PNAS...76..106G }}</ref><ref>{{cite journal |last1=Govender |first1=Kamini |last2=Naicker |first2=Tricia |last3=Lin |first3=Johnson |last4=Baijnath |first4=Sooraj |last5=Chuturgoon |first5=Anil Amichund |last6=Abdul |first6=Naeem Sheik |last7=Docrat |first7=Taskeen |last8=Kruger |first8=Hendrik Gerhardus |last9=Govender |first9=Thavendran |title=A novel and more efficient biosynthesis approach for human insulin production in Escherichia coli (E. coli) |journal=AMB Express |date=December 2020 |volume=10 |issue=1 |page=43 |doi=10.1186/s13568-020-00969-w |doi-access=free |pmc=7062966 |pmid=32152803 }}</ref><ref>{{Cite journal |last1=Zieliński |first1=Marcin |last2=Romanik-Chruścielewska |first2=Agnieszka |last3=Mikiewicz |first3=Diana |last4=Łukasiewicz |first4=Natalia |last5=Sokołowska |first5=Iwona |last6=Antosik |first6=Jarosław |last7=Sobolewska-Ruta |first7=Agnieszka |last8=Bierczyńska-Krzysik |first8=Anna |last9=Zaleski |first9=Piotr |last10=Płucienniczak |first10=Andrzej |date=2019-05-01 |title=Expression and purification of recombinant human insulin from E. coli 20 strain |journal=Protein Expression and Purification |volume=157 |pages=63–69 |doi=10.1016/j.pep.2019.02.002 |pmid=30735706 |doi-access=free }}</ref>

===Gene therapy===
{{main|Vectors in gene therapy}}
Plasmids may also be used for gene transfer as a potential treatment in [[gene therapy]] so that it may express the protein that is lacking in the cells.  Some forms of [[gene therapy]] require the insertion of therapeutic [[gene]]s at pre-selected [[chromosome|chromosomal]] target sites within the human [[genome]]. Plasmid vectors are one of many approaches that could be used for this purpose. [[Zinc finger nuclease]]s (ZFNs) offer a way to cause a site-specific [[double-strand break]] to the DNA genome and cause [[homologous recombination]]. Plasmids encoding ZFN could help deliver a therapeutic gene to a specific site so that [[cell damage]], cancer-causing mutations, or an [[immune response]] is avoided.<ref name= Kandavelou>{{cite book |vauthors=Kandavelou K, Chandrasegaran S |year=2008|chapter=Plasmids for Gene Therapy|title=Plasmids: Current Research and Future Trends|publisher=Caister Academic Press|isbn= 978-1-904455-35-6}}</ref>

===Disease models===
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 in [[adeno-associated virus]] recombination techniques, and [[zinc finger nucleases]], have enabled the creation of a new generation of [[isogenic human disease models]].

=== Biosynthetic Gene Cluster (BGC) ===
Plasmids assist in transporting [[biosynthetic gene cluster]]s - a set of gene that contain all the necessary enzymes that lead to the production of special metabolites (formally known as [[secondary metabolite]]).<ref>{{cite journal | vauthors = Hemmerling F, Piel J | title = Strategies to access biosynthetic novelty in bacterial genomes for drug discovery | journal = Nature Reviews. Drug Discovery | volume = 21 | issue = 5 | pages = 359–378 | date = May 2022 | pmid = 35296832 | doi = 10.1038/s41573-022-00414-6 }}</ref> 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.<ref>{{cite journal | vauthors = Davies J | title = Specialized microbial metabolites: functions and origins | journal = The Journal of Antibiotics | volume = 66 | issue = 7 | pages = 361–364 | date = July 2013 | pmid = 23756686 | doi = 10.1038/ja.2013.61 | doi-access = free }}</ref><ref name=":2" /> Plasmids can contain and express several BGCs with a few plasmids known to be exclusive for transferring BGCs.<ref name=":2">{{cite journal | vauthors = Saati-Santamaría Z | title = Global Map of Specialized Metabolites Encoded in Prokaryotic Plasmids | journal = Microbiology Spectrum | volume = 11 | issue = 4 | pages = e0152323 | date = August 2023 | pmid = 37310275 | pmc = 10434180 | doi = 10.1128/spectrum.01523-23 | editor-first = Olaya | editor-last = Rendueles }}</ref> BGC's can also be transfers to the host organism's chromosome, utilizing a plasmid vector, which allows for studies in gene knockout experiments.<ref>{{cite journal | vauthors = Okino N, Li M, Qu Q, Nakagawa T, Hayashi Y, Matsumoto M, Ishibashi Y, Ito M | title = Two bacterial glycosphingolipid synthases responsible for the synthesis of glucuronosylceramide and α-galactosylceramide | journal = The Journal of Biological Chemistry | volume = 295 | issue = 31 | pages = 10709–10725 | date = July 2020 | pmid = 32518167 | pmc = 7397116 | doi = 10.1074/jbc.RA120.013796 | doi-access = free }}</ref> 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 of [[toxin]]s/antitoxins.<ref>{{cite journal | vauthors = Mara P, Geller-McGrath D, Suter E, Taylor GT, Pachiadaki MG, Edgcomb VP | title = Plasmid-Borne Biosynthetic Gene Clusters within a Permanently Stratified Marine Water Column | journal = Microorganisms | volume = 12 | issue = 5 | page = 929 | date = May 2024 | pmid = 38792759 | pmc = 11123730 | doi = 10.3390/microorganisms12050929 | doi-access = free }}</ref>

==Episomes==
{{main|Episome}}

The term ''episome'' was introduced by [[François Jacob]] and [[Élie Wollman]] in 1958 to refer to extra-chromosomal genetic material that may replicate autonomously or become integrated into the chromosome.<ref>{{cite journal | vauthors = Morange M | title = What history tells us XIX. The notion of the episome | journal = Journal of Biosciences | volume = 34 | issue = 6 | pages = 845–848 | date = December 2009 | pmid = 20093737 | doi = 10.1007/s12038-009-0098-z | s2cid = 11367145 }}</ref><ref>{{citation |vauthors=Jacob F, Wollman EL |year=1958 |title= Les épisomes, elements génétiques ajoutés |journal=Comptes Rendus de l'Académie des Sciences de Paris |volume=247|issue=1 |pages= 154–56 |pmid= 13561654  }}</ref> Since the term was introduced, however, its use has changed, as ''plasmid'' has become the preferred term for autonomously replicating extrachromosomal DNA. At a 1968 symposium in London some participants suggested that the term ''episome'' be abandoned, although others continued to use the term with a shift in meaning.<ref>{{cite book |chapter-url=https://books.google.com/books?id=a1g7Xf4CTygC&pg=PA4 |title=Bacterial Episomes and Plasmids |publisher=CIBA Foundation Symposium | vauthors = Hayes W  |chapter=What are episomes and plasmids? | veditors = Wolstenholme GE, O'Connor M |pages=4–8 |year=1969 |isbn=978-0-7000-1405-7 }}</ref><ref>{{cite book |url=https://books.google.com/books?id=a1g7Xf4CTygC&pg=PA244 |title= Bacterial Episomes and Plasmids |publisher=CIBA Foundation Symposium | veditors = Wolstenholme GE, O'Connor M |pages=244–45 |year=1969 |isbn=978-0-7000-1405-7 }}</ref>

Today, some authors use ''episome'' 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.<ref>{{cite book |url=https://books.google.com/books?id=byoWBAAAQBAJ&pg=PA238 |title=Introduction to Genetics: A Molecular Approach| vauthors = Brown TA |publisher=Garland Science |year= 2011 |page=238 |isbn=978-0-8153-6509-9}}</ref>

In the context of eukaryotes, the term ''episome'' is used to mean a non-integrated extrachromosomal closed circular DNA molecule that may be replicated in the nucleus.<ref>{{cite journal | vauthors = Van Craenenbroeck K, Vanhoenacker P, Haegeman G | title = Episomal vectors for gene expression in mammalian cells | journal = European Journal of Biochemistry | volume = 267 | issue = 18 | pages = 5665–5678 | date = September 2000 | pmid = 10971576 | doi = 10.1046/j.1432-1327.2000.01645.x | doi-access =  }}</ref><ref>{{cite journal | vauthors = Colosimo A, Goncz KK, Holmes AR, Kunzelmann K, Novelli G, Malone RW, Bennett MJ, Gruenert DC | title = Transfer and expression of foreign genes in mammalian cells | journal = BioTechniques | volume = 29 | issue = 2 | pages = 314–18, 320–22, 324 passim | date = August 2000 | pmid = 10948433 | doi = 10.2144/00292rv01 | url = http://www9.georgetown.edu/gumc/departments/pharmacology/courses/Glazer1.pdf | doi-access = free | archive-url = https://web.archive.org/web/20110724082856/http://www9.georgetown.edu/gumc/departments/pharmacology/courses/Glazer1.pdf | archive-date = 24 July 2011 }}</ref> Viruses are the most common examples of this, such as [[herpesviridae|herpesviruses]], [[adenoviruses]], and [[polyomavirus]]es, but some are plasmids.  Other examples include aberrant chromosomal fragments, such as [[double minute|double 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 in [[poxvirus]] infections) can also occur. Some episomes, such as herpesviruses, replicate in a [[rolling circle]] mechanism, similar to [[bacteriophage]]s (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, including [[Epstein-Barr virus]] and [[Kaposi's sarcoma-associated herpesvirus]], are maintained as latent, chromosomally distinct episomes in cancer cells, where the viruses express [[oncogenes]] that promote cancer cell proliferation.  In cancers, these episomes passively replicate together with host chromosomes when the cell divides.  When these viral episomes initiate [[lytic cycle|lytic replication]] to generate multiple virus particles, they generally activate cellular [[innate immunity]] defense mechanisms that kill the host cell.

==Plasmid maintenance==
{{main|Addiction module}}
Some plasmids or microbial hosts include an [[addiction module|addiction system]] or postsegregational killing system (PSK), such as the [[hok/sok system|hok/sok]] (host killing/suppressor of killing) system of plasmid R1 in ''[[Escherichia coli]]''.<ref>{{cite journal | vauthors = Gerdes K, Rasmussen PB, Molin S | title = Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 10 | pages = 3116–3120 | date = May 1986 | pmid = 3517851 | pmc = 323463 | doi = 10.1073/pnas.83.10.3116 | doi-access = free | bibcode = 1986PNAS...83.3116G }}</ref> This variant produces both a long-lived [[poison]] and a short-lived [[antidote]]. Several types of plasmid addiction systems (toxin/ antitoxin, metabolism-based, ORT systems) were described in the [[literature]]<ref>{{cite journal | vauthors = Kroll J, Klinter S, Schneider C, Voss I, Steinbüchel A | title = Plasmid addiction systems: perspectives and applications in biotechnology | journal = Microbial Biotechnology | volume = 3 | issue = 6 | pages = 634–657 | date = November 2010 | pmid = 21255361 | pmc = 3815339 | doi = 10.1111/j.1751-7915.2010.00170.x }}</ref> 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|reason=The productivity of what? Enhanced by what? Is this sentence placed here by mistake?|date=October 2024}}

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.

== Plasmids in eukaryotes ==
Plasmids replicated and expressed by the eukaryotic cell's machinery may reside in the [[cytoplasm]] or the [[cell nucleus]], with different plasmids having different preferences. In addition, eukaryotes have two endosymbiotic organelles with their own genome and genetic machinery &ndash; the [[mitochondrion]] and the [[chloroplast]] &ndash; and each of these can carry plasmids in addition to the main organellar genome molecule.

=== Eukaryotic cytoplasmic plasmids ===
==== Yeast cytoplasmic plasmids ====
The natural linear pGKL plasmids from ''[[Kluyveromyces lactis]]'' are responsible for [[killer phenotypes]]. They can be put into the common baker's yeast ''S. cerevisiae''.<ref>{{cite journal | vauthors = Gunge N, Murata K, Sakaguchi K | title = Transformation of Saccharomyces cerevisiae with linear DNA killer plasmids from Kluyveromyces lactis | journal = Journal of Bacteriology | volume = 151 | issue = 1 | pages = 462–464 | date = July 1982 | pmid = 7045080 | pmc = 220260 | doi = 10.1128/JB.151.1.462-464.1982 }}</ref>

=== Eukaryotic nuclear plasmids ===
Plasmids enter the nucleus during cell division, being rolled up in the [[nuclear envelope]] as it is reformed. As a result, nuclear plasmids do not work in non-dividing cells.<ref>{{cite journal |last1=Haraguchi |first1=Tokuko |last2=Koujin |first2=Takako |last3=Shindo |first3=Tomoko |last4=Bilir |first4=Şükriye |last5=Osakada |first5=Hiroko |last6=Nishimura |first6=Kohei |last7=Hirano |first7=Yasuhiro |last8=Asakawa |first8=Haruhiko |last9=Mori |first9=Chie |last10=Kobayashi |first10=Shouhei |last11=Okada |first11=Yasushi |last12=Chikashige |first12=Yuji |last13=Fukagawa |first13=Tatsuo |last14=Shibata |first14=Shinsuke |last15=Hiraoka |first15=Yasushi |title=Transfected plasmid DNA is incorporated into the nucleus via nuclear envelope reformation at telophase |journal=Communications Biology |date=20 January 2022 |volume=5 |issue=1 |page=78 |doi=10.1038/s42003-022-03021-8|pmid=35058555 |pmc=8776997 }}</ref>

==== Yeast nuclear plasmids ====
The natural 2 micron plasmid (named after the fact that it is about 2&nbsp;μm in size) is found in the common baker's yeast ''S. cerevisiae''. It resides in the nucleus in 30&ndash;40 copies per cell. It is often modified for [[genetic engineering]] of yeast.<ref>{{cite journal |last1=Chan |first1=KM |last2=Liu |first2=YT |last3=Ma |first3=CH |last4=Jayaram |first4=M |last5=Sau |first5=S |title=The 2 micron plasmid of Saccharomyces cerevisiae: a miniaturized selfish genome with optimized functional competence. |journal=Plasmid |date=July 2013 |volume=70 |issue=1 |pages=2–17 |doi=10.1016/j.plasmid.2013.03.001 |pmid=23541845}}</ref>

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. They are usually modified into cloning vectors when studying the functionality of a solo gene or when the gene is toxic. Also connected with the gene URA3 which 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.

==== Mammalian nuclear plasmids ====
Artificial plasmids are put into mammalian cells to make them produce a certain gene product. They are also used to identify and quantitatively study [[regulatory element]]s, with the assumption that these elements on a plasmid would act similarly to a copy on the chromosome.<ref name=Mallory25/>

==== Interaction with chromatin ====
Being DNA sequences in the nucleus, the plasmid molecule also interactes with [[histone]] proteins.
* In yeast, pBR327 produces well-formed [[chromatin]] thanks to the alignment of [[nucleosome]]s by Histone H5. A specific 800bp region is found to induce this alignment, without which it does not occur.<ref>{{cite journal |last1=Jeong |first1=SW |last2=Lauderdale |first2=JD |last3=Stein |first3=A |title=Chromatin assembly on plasmid DNA in vitro. Apparent spreading of nucleosome alignment from one region of pBR327 by histone H5. |journal=Journal of Molecular Biology |date=20 December 1991 |volume=222 |issue=4 |pages=1131–47 |doi=10.1016/0022-2836(91)90597-y |pmid=1662288}}</ref>
* Mammals: the HEK 293 cell forms nucleosomes around both intact and damaged pEGFP-N1, but the structure is anomalous compared to proper chromatin from chromosomes.<ref>{{cite journal |last1=Mladenova |first1=V. |last2=Mladenov |first2=E. |last3=Russev |first3=G. |title=Organization of Plasmid DNA into Nucleosome-Like Structures after Transfection in Eukaryotic Cells |journal=Biotechnology & Biotechnological Equipment |date=January 2009 |volume=23 |issue=1 |pages=1044–1047 |doi=10.1080/13102818.2009.10817609}}</ref> In 2025, it was discovered that formation of chromatin is guided by the sequences of the plasmid (like it is on the chromosome), but only some sequences produce the "native" structure as found on the chromosome.<ref name=Mallory25>{{cite bioRxiv |biorxiv=10.1101/2025.05.27.656122 |title=Principles and functional consequences of plasmid chromatinization in mammalian cells |date=2025 | vauthors = Mallory BJ, Tullius TW, Biar CG, Gustafson JA, Bohaczuk SC, Dubocanin D, Starita LM, Stergachis AB}}</ref>

=== Eukaryotic organellar plasmids ===
==== Natural plant mitochondrial plasmids ====
The mitochondria of many higher plants contain [[Replicon (genetics)|self-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.<ref name="Gualberto-2014">{{cite journal | vauthors = Gualberto JM, Mileshina D, Wallet C, Niazi AK, Weber-Lotfi F, Dietrich A | title = The plant mitochondrial genome: dynamics and maintenance | journal = Biochimie | volume = 100 | pages = 107–120 | date = May 2014 | pmid = 24075874 | doi = 10.1016/j.biochi.2013.09.016 }}</ref> Circular plasmids have been isolated and found in many different plants, with those in ''[[Vicia faba]] and [[Chenopodium album]]'' being the most studied and whose mechanism of replication is known. The circular plasmids can replicate using the θ model of replication (as in ''Vicia faba'') and through [[rolling circle replication]] (as in ''C.album'').<ref>{{cite journal | vauthors = Backert S, Meissner K, Börner T | title = Unique features of the mitochondrial rolling circle-plasmid mp1 from the higher plant Chenopodium album (L.) | journal = Nucleic Acids Research | volume = 25 | issue = 3 | pages = 582–589 | date = February 1997 | pmid = 9016599 | pmc = 146482 | doi = 10.1093/nar/25.3.582 }}</ref> Linear plasmids have been identified in some plant species such as ''[[Beta vulgaris]]'', ''[[Brassica napus]], [[Maize|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 through [[horizontal gene transfer]] from pathogenic fungi.<ref name="Gualberto-2014" /><ref>{{cite journal | vauthors = Handa H | title = Linear plasmids in plant mitochondria: peaceful coexistences or malicious invasions? | journal = Mitochondrion | volume = 8 | issue = 1 | pages = 15–25 | date = January 2008 | pmid = 18326073 | doi = 10.1016/j.mito.2007.10.002 }}</ref>

== Study of plasmids ==

=== Plasmid DNA extraction ===
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 for [[cloning#Molecular cloning|molecular cloning]], plasmids often need to be isolated.

There are several methods to [[plasmid preparation|isolate plasmid DNA]] from bacteria, ranging from the plasmid extraction kits ([[Plasmid preparation#Preparations by size|miniprep to the maxiprep or bulkprep]]), [[alkaline lysis]], enzymatic lysis, and mechanical lysis  .<ref name="Molecular cloning"/> 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 by [[restriction 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.

=== Conformations ===
Plasmid DNA may appear in one of five conformations, which (for a given size) run at different speeds in a gel during [[agarose gel electrophoresis|electrophoresis]]. The conformations are listed below in order of electrophoretic mobility (speed for a given applied voltage) from slowest to fastest:
* ''[[Nick (DNA)|Nicked open-circular]]'' DNA has one strand cut.
* ''Relaxed circular'' DNA is fully intact with both strands uncut but has been enzymatically ''relaxed'' (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 linear ''in vivo''. This can be modeled with an electrical extension cord that is not plugged into itself.
* ''[[DNA supercoil|Supercoiled]]'' (or ''covalently 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 an [[extension cord]] and then plugging it into itself.
* ''Supercoiled [[denaturation (biochemistry)|denatured]]'' DNA is similar to ''supercoiled 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 digest]]s are frequently used to analyse purified plasmids. These enzymes specifically break the DNA at certain short sequences. The resulting linear fragments form 'bands' after [[gel 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.

=== Software for bioinformatics and design ===
{{main|List of genetic engineering software}}

The use of plasmids as a technique in [[molecular biology]] is supported by [[bioinformatics]] [[software]]. These programs record the [[DNA]] sequence of plasmid vectors, help to predict cut sites of [[restriction enzymes]], and to plan manipulations. Examples of software packages that handle plasmid maps are ApE, [[Clone manager|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.<ref>{{cite web |url=http://vimeo.com/57923864 |title=Vector NTI feedback video |work= The DNA Lab }}</ref>

=== Plasmid collections ===
Many plasmids have been created over the years and researchers have given out plasmids to plasmid databases such as the non-profit organisations [https://www.addgene.org Addgene] and [https://bccm.belspo.be/about-GeneCorner BCCM/GeneCorner]. One can find and request plasmids from those databases for research.
Researchers also often upload plasmid sequences to the [https://www.ncbi.nlm.nih.gov/nuccore/ NCBI 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 Orlek ''et al'',<ref>{{cite journal |last1=Orlek |first1=Alex |last2=Phan |first2=Hang |last3=Sheppard |first3=Anna E. |last4=Doumith |first4=Michel |last5=Ellington |first5=Matthew |last6=Peto |first6=Tim |last7=Crook |first7=Derrick |last8=Walker |first8=A. Sarah |last9=Woodford |first9=Neil |last10=Anjum |first10=Muna F. |last11=Stoesser |first11=Nicole |title=A curated dataset of complete Enterobacteriaceae plasmids compiled from the NCBI nucleotide database |journal=Data in Brief |date=June 2017 |volume=12 |pages=423–426 |doi=10.1016/j.dib.2017.04.024 |pmc=5426034 |pmid=28516137 |bibcode=2017DIB....12..423O }}</ref> which limited itself to ''[[Enterobacteriaceae]]'' plasmids, while COMPASS also encompassed plasmids from other bacteria. More recently, PLSDB<ref>{{cite journal |last1=Schmartz |first1=Georges P |last2=Hartung |first2=Anna |last3=Hirsch |first3=Pascal |last4=Kern |first4=Fabian |last5=Fehlmann |first5=Tobias |last6=Müller |first6=Rolf |last7=Keller |first7=Andreas |title=PLSDB: advancing a comprehensive database of bacterial plasmids |journal=Nucleic Acids Research |date=7 January 2022 |volume=50 |issue=D1 |pages=D273–D278 |doi=10.1093/nar/gkab1111 |pmc=8728149 |pmid=34850116 }}</ref> was made as a more up to date curated database of NCBI plasmids, and as of 2024 contains over 72,000 entries.<ref>{{cite journal |last1=Molano |first1=Leidy-Alejandra G |last2=Hirsch |first2=Pascal |last3=Hannig |first3=Matthias |last4=Müller |first4=Rolf |last5=Keller |first5=Andreas |title=The PLSDB 2025 update: enhanced annotations and improved functionality for comprehensive plasmid research |journal=Nucleic Acids Research |date=6 January 2025 |volume=53 |issue=D1 |pages=D189–D196 |doi=10.1093/nar/gkae1095 |pmc=11701622 |pmid=39565221 }}</ref> A similar database is pATLAS, which additionally includes visual analytics tools to show relationships between plasmids.<ref>{{cite journal |last1=Jesus |first1=Tiago F |last2=Ribeiro-Gonçalves |first2=Bruno |last3=Silva |first3=Diogo N |last4=Bortolaia |first4=Valeria |last5=Ramirez |first5=Mário |last6=Carriço |first6=João A |title=Plasmid ATLAS: plasmid visual analytics and identification in high-throughput sequencing data |journal=Nucleic Acids Research |date=8 January 2019 |volume=47 |issue=D1 |pages=D188–D194 |doi=10.1093/nar/gky1073 |pmc=6323984 |pmid=30395323 }}</ref> 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 from [[Metagenomics|metagenomes]] and metatranscriptomes.<ref>{{cite journal |last1=Camargo |first1=Antonio Pedro |last2=Call |first2=Lee |last3=Roux |first3=Simon |last4=Nayfach |first4=Stephen |last5=Huntemann |first5=Marcel |last6=Palaniappan |first6=Krishnaveni |last7=Ratner |first7=Anna |last8=Chu |first8=Ken |last9=Mukherjeep |first9=Supratim |last10=Reddy |first10=T B K |last11=Chen |first11=I-Min A |last12=Ivanova |first12=Natalia N |last13=Eloe-Fadrosh |first13=Emiley A |last14=Woyke |first14=Tanja |last15=Baltrus |first15=David A |last16=Castañeda-Barba |first16=Salvador |last17=de la Cruz |first17=Fernando |last18=Funnell |first18=Barbara E |last19=Hall |first19=James P J |last20=Mukhopadhyay |first20=Aindrila |last21=Rocha |first21=Eduardo P C |last22=Stalder |first22=Thibault |last23=Top |first23=Eva |last24=Kyrpides |first24=Nikos C |title=IMG/PR: a database of plasmids from genomes and metagenomes with rich annotations and metadata |journal=Nucleic Acids Research |date=5 January 2024 |volume=52 |issue=D1 |pages=D164–D173 |doi=10.1093/nar/gkad964 |pmc=10767988 |pmid=37930866 }}</ref>

Other datasets have been created by sequencing and computing plasmid genomes from pre-existing bacterial collections, e.g. the NORM collection<ref>{{Cite journal |last1=Gladstone |first1=Rebecca A. |last2=McNally |first2=Alan |last3=Pöntinen |first3=Anna K. |last4=Tonkin-Hill |first4=Gerry |last5=Lees |first5=John A. |last6=Skytén |first6=Kusti |last7=Cléon |first7=François |last8=Christensen |first8=Martin O. K. |last9=Haldorsen |first9=Bjørg C. |last10=Bye |first10=Kristina K. |last11=Gammelsrud |first11=Karianne W. |last12=Hjetland |first12=Reidar |last13=Kümmel |first13=Angela |last14=Larsen |first14=Hege E. |last15=Lindemann |first15=Paul Christoffer |date=2021-07-01 |title=Emergence and dissemination of antimicrobial resistance in Escherichia coli causing bloodstream infections in Norway in 2002–17: a nationwide, longitudinal, microbial population genomic study |journal=The Lancet Microbe |language=English |volume=2 |issue=7 |pages=e331–e341 |doi=10.1016/S2666-5247(21)00031-8 |pmc=7614948 |pmid=35544167}}</ref><ref>{{cite bioRxiv |biorxiv=10.1101/2023.10.14.562336 |title=Plasmid-driven strategies for clone success in ''Escherichia coli'' |date=2024 |last1=Arredondo-Alonso |first1=Sergio |last2=Pöntinen |first2=Anna K. |last3=Gama |first3=João Alves |last4=Gladstone |first4=Rebecca A. |last5=Harms |first5=Klaus |last6=Tonkin-Hill |first6=Gerry |last7=Thorpe |first7=Harry A. |last8=Simonsen |first8=Gunnar S. |last9=Samuelsen |first9=Ørjan |last10=Johnsen |first10=Pål J. |last11=Corander |first11=Jukka }}</ref> and the Murray Collection.<ref>{{cite journal |last1=Baker |first1=Kate S. |last2=Burnett |first2=Edward |last3=McGregor |first3=Hannah |last4=Deheer-Graham |first4=Ana |last5=Boinett |first5=Christine |last6=Langridge |first6=Gemma C. |last7=Wailan |first7=Alexander M. |last8=Cain |first8=Amy K. |last9=Thomson |first9=Nicholas R. |last10=Russell |first10=Julie E. |last11=Parkhill |first11=Julian |title=The Murray collection of pre-antibiotic era Enterobacteriacae: a unique research resource |journal=Genome Medicine |date=December 2015 |volume=7 |issue=1 |page=97 |doi=10.1186/s13073-015-0222-7 |doi-broken-date=1 July 2025 |doi-access=free |pmc=4584482 |pmid=26411565 }}</ref><ref>{{cite bioRxiv |biorxiv=10.1101/2024.09.03.610986 |title=Pre and Post antibiotic epoch: Insights into the historical spread of antimicrobial resistance |date=2024 |last1=Cazares |first1=Adrian |last2=Figueroa |first2=Wendy |last3=Cazares |first3=Daniel |last4=Lima |first4=Leandro |last5=Turnbull |first5=Jake D. |last6=McGregor |first6=Hannah |last7=Dicks |first7=Jo |last8=Alexander |first8=Sarah |last9=Iqbal |first9=Zamin |last10=Thomson |first10=Nicholas R. }}</ref>

=== mRNA vaccines ===
In 2025, researchers from Canada and the US revealed that Covid-19 mRNA vaccines contain high amounts of residual DNA (371-1,548 ng/dose for Pfizer and 1,130-6,280 for Moderna), far exceeding the maximum level (10 ng/dose) that was recommended from the [[WHO]] and the [[FDA]]. SV40 sequences were observed in Pfizer products. They also analyzed data from [[VERS]] to examine an association between serious adverse events (SAEs) and mRNA products, suggesting a positive correlation between SAEs and residual DNA levels. The study concluded that transparent information about manufacturing processes should be provided by regulators and industry, and stricter guidelines should be set for safety.<ref> 
{{cite journal 
| title = Quantification of residual plasmid DNA and SV40 promoter-enhancer sequences in Pfizer/BioNTech and Moderna modRNA COVID-19 vaccines from Ontario, Canada
| journal = Autoimmunity 
| date = 2025 
| doi = 10.1080/08916934.2025.2551517
| vauthors = ((Speicher, D. J. et al.)) 
| doi-access = free 
}}
</ref>

== See also ==
{{cmn|
* [[Bacterial artificial chromosome]]
* [[Bacteriophage]]
* [[Recombinant DNA|DNA recombination]]
* [[Plasmidome]]
* [[Provirus]]
* [[Secondary chromosome]]
* [[Segrosome]]
* [[Transposon]]
* [[Triparental mating]]
* [[VectorDB]]
}}

== References ==
{{Reflist}}

== Further reading ==
=== General works ===
{{refbegin}}
* {{cite book | vauthors = Klein DW, Prescott LM, Harley J |title=Microbiology |publisher=WCB/McGraw-Hill |location=Boston |year=1999 }}
* {{cite book | vauthors = Moat AG, Foster JW, Spector MP |title=Microbial Physiology | publisher=Wiley-Liss | year=2002 |isbn=978-0-471-39483-9}}
* {{cite book | vauthors = Smith CU | chapter = Chapter 5: Manipulating Biomolecules | chapter-url = https://books.google.com/books?id=wey2dH3D0SkC&pg=PA110 |title=Elements of Molecular Neurobiology |edition=3rd |publisher=Wiley |pages=101–11 |date=2002 |location=Chichester, West Sussex, England | isbn = 978-0-470-85717-5 }}
{{refend}}

===Episomes===
{{refbegin|32em}}
* {{cite journal | vauthors = Piechaczek C, Fetzer C, Baiker A, Bode J, Lipps HJ | title = A vector based on the SV40 origin of replication and chromosomal S/MARs replicates episomally in CHO cells | journal = Nucleic Acids Research | volume = 27 | issue = 2 | pages = 426–428 | date = January 1999 | pmid = 9862961 | pmc = 148196 | doi = 10.1093/nar/27.2.426 }}
* {{cite journal | vauthors = Bode J, Fetzer CP, Nehlsen K, Scinteie M, Hinrichsen BH, Baiker A, Piechazcek C, Benham C, Lipps HJ |title=The Hitchhiking principle: Optimizing episomal vectors for the use in gene therapy and biotechnology |journal=Gene Therapy and Molecular Biology |volume=6 |pages=33–46 | date = January 2001 |url=http://www.gtmb.org/VOL6A/GTMBVOL6APDF/INDIVIDUAL/03%20%20Bode.pdf |archive-url=https://web.archive.org/web/20090530141241/http://www.gtmb.org/VOL6A/GTMBVOL6APDF/INDIVIDUAL/03%20%20Bode.pdf |archive-date=30 May 2009 }}
* {{cite journal | vauthors = Nehlsen K, Broll S, Bode J | title = Replicating minicircles: Generation of nonviral episomes for the efficient modification of dividing cells | journal = Gene Ther Mol Biol | volume = 10 | pages = 233–44 | year = 2006 | url = http://www.gtmb.org/VOL10B/INDIVIDUAL/25.%20Nehlsen%20et%20al,%20233-244.pdf | archive-url = https://web.archive.org/web/20090530141235/http://www.gtmb.org/VOL10B/INDIVIDUAL/25.%20Nehlsen%20et%20al%2C%20233-244.pdf | archive-date = 30 May 2009 }}
* {{cite journal | vauthors = Ehrhardt A, Haase R, Schepers A, Deutsch MJ, Lipps HJ, Baiker A | title = Episomal vectors for gene therapy | journal = Current Gene Therapy | volume = 8 | issue = 3 | pages = 147–161 | date = June 2008 | pmid = 18537590 | doi = 10.2174/156652308784746440 | url = http://www.benthamdirect.org/pages/content.php?CGT/2008/00000008/00000003/0001Q.SGM | archive-url = https://web.archive.org/web/20110926182142/http://www.benthamdirect.org/pages/content.php?CGT%2F2008%2F00000008%2F00000003%2F0001Q.SGM | archive-date = 26 September 2011 | url-access = subscription }}
* {{cite journal | vauthors = Argyros O, Wong SP, Niceta M, Waddington SN, Howe SJ, Coutelle C, Miller AD, Harbottle RP | title = Persistent episomal transgene expression in liver following delivery of a scaffold/matrix attachment region containing non-viral vector | journal = Gene Therapy | volume = 15 | issue = 24 | pages = 1593–1605 | date = December 2008 | pmid = 18633447 | doi = 10.1038/gt.2008.113 | doi-access = free }}
* {{cite journal | vauthors = Wong SP, Argyros O, Coutelle C, Harbottle RP | title = Strategies for the episomal modification of cells | journal = Current Opinion in Molecular Therapeutics | volume = 11 | issue = 4 | pages = 433–441 | date = August 2009 | pmid = 19649988 | url = http://www.biomedcentral.com/1464-8431/11/433/abstract | archive-url = https://web.archive.org/web/20110917140204/http://www.biomedcentral.com/1464-8431/11/433/abstract | archive-date = 17 September 2011 }}
* {{cite journal | vauthors = Haase R, Argyros O, Wong SP, Harbottle RP, Lipps HJ, Ogris M, Magnusson T, Vizoso Pinto MG, Haas J, Baiker A | title = pEPito: a significantly improved non-viral episomal expression vector for mammalian cells | journal = BMC Biotechnology | volume = 10 | article-number = 20 | date = March 2010 | pmid = 20230618 | pmc = 2847955 | doi = 10.1186/1472-6750-10-20 | doi-access = free }}
{{refend}}

== External links ==
* [http://www.ispb.org/ International Society for Plasmid Biology and other Mobile Genetic Elements]
* [https://www.whatisbiotechnology.org/index.php/science/summary/plasmid/ What is Biotechnology]
* [https://web.archive.org/web/20090310010107/http://histmicro.yale.edu/mainfram.htm History of Plasmids with timeline]

{{Self-replicating organic structures}}
{{Organisms et al.}}
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[[Category:Gene delivery]]
[[Category:Mobile genetic elements]]
[[Category:Molecular biology]]
[[Category:Molecular biology techniques]]
[[Category:Prokaryotic cell anatomy]]