Editing Inverted repeat

{{Short description|Nucleic acid sequence}}
An '''inverted repeat''' (or '''IR''') is a single stranded sequence of [[nucleotide]]s followed downstream by its [[complementarity (molecular biology)|reverse complement]].<ref name="Ussery2008">{{cite book |title=Computing for Comparative Microbial Genomics: Bioinformatics for Microbiologists |chapter=Word Frequencies, Repeats, and Repeat-related Structures in Bacterial Genomes |series=Computational Biology |volume=8 |pages=133–144 |first1=David W. |last1=Ussery |first2=Trudy |last2=Wassenaar |first3=Stefano |last3=Borini |publisher=Springer |edition=1 |date=2008-12-22 |isbn=978-1-84800-254-8}}</ref> The intervening sequence of nucleotides between the initial sequence and the reverse complement can be any length including zero. For example, {{color|blue|5'---TTACGnnnnnn}}{{color|green|CGTAA---3'}} is an inverted repeat sequence. When the intervening length is zero, the composite sequence is a [[palindromic sequence]].<ref>{{cite journal | pmid=25409465 |  doi= 10.1371/journal.pone.0113349 |title= detectIR: A Novel Program for Detecting Perfect and Imperfect Inverted Repeats Using Complex Numbers and Vector Calculation |first1= Congting |last1= Ye |first2= Guoli |last2= Ji |first3= Chun |last3= Liang |year= 2014 |journal= PLOS ONE |volume= 9 |issue= 11 |page= e113349| pmc= 4237412 | bibcode= 2014PLoSO...9k3349Y | doi-access= free }}</ref>

Both inverted repeats and [[direct repeat]]s constitute types of [[Nucleic acid sequence|nucleotide sequences]] that occur repetitively. <!--The [[human genome]] has many nucleotide sequences that occur repeatedly and as such, can be grouped in two simple classes: repetitive and unique sequences.<ref name=Eichler />-->  These [[repeated sequence (DNA)|repeated DNA sequences]] often range from a pair of nucleotides to a whole [[gene]], while the proximity of the repeat sequences varies between widely dispersed and simple [[tandemly arrayed genes|tandem arrays]].<ref name=Sutherland>{{cite journal|last=Richards|first=GR|author2=Richards, RI|title=Simple tandem DNA repeats and human genetic disease|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Apr 25, 1995|volume=92|issue=9|pages=3636–41|pmid=7731957|bibcode=1995PNAS...92.3636S|doi=10.1073/pnas.92.9.3636|pmc=42017|doi-access=free}}</ref> The short [[tandem repeat]] sequences may exist as just a few copies in a small region to thousands of copies dispersed all over the genome of most [[eukaryotes]].<ref name=VAN>{{cite journal|last=van Belkum|first=A |author2=Scherer, S |author3=van Alphen, L |author4=Verbrugh, H|title=Short-sequence DNA repeats in prokaryotic genomes|journal=Microbiology and Molecular Biology Reviews|date=June 1998|volume=62|issue=2|pages=275–93|doi=10.1128/MMBR.62.2.275-293.1998 |pmid=9618442|pmc=98915}}</ref> Repeat sequences with about 10–100 [[base pair]]s are known as [[minisatellite]]s, while shorter repeat sequences having mostly 2–4 base pairs are known as [[microsatellite]]s.<ref name=Ramel>{{cite journal|last=Ramel|first=C|title=Mini- and microsatellites|journal=Environmental Health Perspectives|date=June 1997|volume=105|pages=781–9|pmid=9255562|pmc=1470042|issue=Suppl 4|doi=10.2307/3433284|jstor=3433284}}</ref>  The most common repeats include the dinucleotide repeats, which have the [[nitrogenous base|bases]] AC on one DNA strand, and GT on the complementary strand.<ref name=Sutherland /> Some elements of the [[genome]] with unique sequences function as [[exons]], [[introns]] and regulatory DNA.<ref name=Eichler>{{cite journal|last=Eichler|first=EE|title=Masquerading repeats: paralogous pitfalls of the human genome|journal=Genome Research|date=August 1998|volume=8|issue=8|pages=758–62|pmid=9724321|doi=10.1101/gr.8.8.758 |doi-access=free}}</ref> Though the most familiar loci of the repetitive sequences are the [[centromere]] and the [[telomere]],<ref name=Eichler /> a large portion of the repeated sequences in the genome are found among the [[noncoding DNA]].<ref name=Ramel />

Inverted repeats have a number of important biological functions.  They define the boundaries in [[transposon]]s and indicate regions capable of self-complementary [[base pairing]] (regions within a single sequence which can base pair with each other). These properties play an important role in genome instability<ref name=Voineagu /> and contribute not only to [[cellular evolution]] and [[genetic diversity]]<ref>{{cite journal|last=Lin|first=CT|author2=Lin, WH |author3=Lyu, YL |author4= Whang-Peng, J |title=Inverted repeats as genetic elements for promoting DNA inverted duplication: implications in gene amplification|journal=Nucleic Acids Research|date=Sep 1, 2001|volume=29|issue=17|pages=3529–38|pmid=11522822|doi=10.1093/nar/29.17.3529|pmc=55881}}</ref> but also to [[mutation]] and [[disease]].<ref name=bissler />  In order to study these effects in detail, a number of programs and databases have been developed to assist in discovery and annotation of inverted repeats in various genomes.

==Understanding inverted repeats==

===Example of an inverted repeat===
[[File:Inverted-Repeat.gif|thumb|500px|left|The 5 base-pair sequence on the left is "repeated" and "inverted" to form sequence on the right.]]

Beginning with this initial sequence:<br />
&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; {{color|blue|5'-TTACG-3'}}

The complement created by base pairing is:<br />
&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; {{color|green|3'-AATGC-5'}}

The reverse complement is:<br />
&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; {{color|green|5'-CGTAA-3'}}

And, the inverted repeat sequence is:<br />
&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; {{color|blue|5'---TTACGnnnnnn}}{{color|green|CGTAA---3'}}

"nnnnnn" represents any number of intervening nucleotides.
{{Clear}}
<!--
===Direct repeat vs. inverted repeat===
A well-defined direct repeat is that which has a duplicated sequence as follows:<ref name=Bissler>{{cite journal|last=Bissler|first=JJ|title=DNA inverted repeats and human disease.|journal=Frontiers in Bioscience|date=Mar 27, 1998|volume=3|pages=d408-18|pmid=9516381|doi=10.2741/a284}}</ref> 
:::{{color|blue|5´ '''ACATACA'''ACATACA 3´}}
:::{{color|green|3´ '''TGTATGT'''TGTATGT 5´}}
The nucleotide sequence written in bold characters signifies the repeated sequence.<ref name=Bissler>{{cite journal}}</ref> Linguistically, a typical direct repeat is comparable to saying "bye-bye".<ref name=Bissler>{{cite journal}}</ref> There is similarity between direct and inverted repeat, or else a palindrome, with the exception of the second half of the inverted repeat positioned in the complementary strand as follows:<ref name=Bissler>{{cite journal}}</ref> 
:::{{color|blue|5´ '''ACATACG'''CGTATGT 3´}}
:::{{color|green|3´ TGTATGC'''GCATACA''' 5´}}
The last repeats suggest that palindromes can be related linguistically to a string of characters that reads the same in both directions, such as "level". In all, repeated sequence without the [[complementarity (molecular biology)|reverse complement]] and without inversion, is a [[direct repeat]].<ref name=Ussery2008 /> Based on the same initial sequence discussed above in the section titled "understanding inverted repeats", a direct repeat would be: {{color|blue|5' TTACGnnnnnnTTACG 3'}}
-->

===Vs. direct repeat===
A direct repeat occurs when a sequence is repeated with the same pattern downstream.<ref name=Ussery2008 />  There is no inversion and no reverse complement associated with a direct repeat. The nucleotide sequence written in bold characters signifies the repeated sequence. It may or may not have intervening nucleotides.
:::{{color|blue |5´ '''TTACG'''nnnnnnTTACG 3´}}
:::{{color|green|3´ '''AATGC'''nnnnnnAATGC 5´}}
Linguistically, a typical direct repeat is comparable to rhyming, as in "t'''ime''' on a d'''ime'''".

===Vs. tandem repeat===
A direct repeat with ''no'' intervening nucleotides between the initial sequence and its downstream copy is a [[Tandem repeat]]. The nucleotide sequence written in bold characters signifies the repeated sequence.
:::{{color|blue |5´ '''TTACG'''TTACG 3´}}
:::{{color|green|3´ '''AATGC'''AATGC 5´}}
Linguistically, a typical tandem repeat is comparable to stuttering, or deliberately repeated words, as in "bye-bye".

===Vs. palindrome===
{{main|Palindromic sequence}}
An inverted repeat sequence with ''no'' intervening nucleotides between the initial sequence and its downstream [[complementarity (molecular biology)|reverse complement]] is a [[palindromic sequence|palindrome]].<ref name=Ussery2008 /> <br />&nbsp; &nbsp; EXAMPLE:<br />
&nbsp; &nbsp; &nbsp; &nbsp; Step 1: start with an inverted repeat: {{color|blue|5' TTACGnnnnnnCGTAA 3'}}<br />
&nbsp; &nbsp; &nbsp; &nbsp; Step 2: remove intervening nucleotides: {{color|blue|5' TTACGCGTAA 3'}}<br />
&nbsp; &nbsp; &nbsp; &nbsp; This resulting sequence is palindromic because it is the reverse complement of itself.<ref name=Ussery2008 />
:::{{color|blue|5' TTACGCGTAA 3'}} &nbsp; test sequence (from Step 2 with intervening nucleotides removed)
:::{{color|green|3' AATGCGCATT 5'}} &nbsp; complement of test sequence
:::{{color|blue|5' TTACGCGTAA 3'}} &nbsp; reverse complement &nbsp; &nbsp; This is the same as the test sequence above, and thus, it is a palindrome.

==Biological features and functionality==
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===Origin of inverted repeats===
:This section is "under construction" and will be completed by mid-December.
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===Conditions that favor synthesis===
The diverse genome-wide repeats are derived from [[transposable element]]s, which are now understood to "jump" about different genomic locations, without transferring their original copies.<ref name=Watson>{{cite book|last=School|first=James D. Watson, Cold Spring Harbor Laboratory, Tania A. Baker, Massachusetts Institute of Technology, Stephen P. Bell, Massachusetts Institute of Technology, Alexander Gann, Cold Spring Harbor Laboratory, Michael Levine, University of California, Berkeley, Richard Losik, Harvard University; with Stephen C. Harrison, Harvard Medical|title=Molecular biology of the gene|publisher=Benjamin-Cummings Publishing Company|location=Boston|isbn=9780321762436|edition=Seventh|year=2014}}</ref> Subsequent shuttling of the same sequences over numerous generations ensures their multiplicity throughout the genome.<ref name=Watson /> The limited [[Genetic recombination|recombination]] of the sequences between two distinct sequence elements known as [[Site-specific recombination|conservative site-specific recombination]] (CSSR) results in inversions of the DNA segment, based on the arrangement of the recombination recognition sequences on the donor DNA and recipient DNA.<ref name=Watson /> Again, the orientation of two of the recombining sites within the donor DNA molecule relative to the asymmetry of the intervening DNA cleavage sequences, known as the crossover region, is pivotal to the formation of either inverted repeats or direct repeats.<ref name=Watson /> Thus, recombination occurring at a pair of inverted sites will invert the DNA sequence between the two sites.<ref name=Watson /> <!--Very stable chromosomes have been observed with a comparatively fewer number of inverted repeats than direct repeats, suggesting a relationship between the stability of and the number of  repeats.-->Very stable chromosomes have been observed with comparatively fewer numbers of inverted repeats than direct repeats, suggesting a relationship between chromosome stability and the number of repeats.<ref name=Achaz>{{cite journal|last=Achaz|first=G|author2=Coissac, E |author3=Netter, P |author4= Rocha, EP |title=Associations between inverted repeats and the structural evolution of bacterial genomes|journal=Genetics|date=August 2003|volume=164|issue=4|pages=1279–89|doi=10.1093/genetics/164.4.1279|pmid=12930739|pmc=1462642}}</ref>
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===Most common biological functions using Inverted Repeats===
:This section is "under construction" and will be completed by mid-December.
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===Regions where presence is obligatory===
Terminal inverted repeats have been observed in the DNA of various eukaryotic transposons, even though their source remains unknown.<ref name=Zhang>{{cite journal|last=Zhang|first=HH|author2=Xu, HE |author3=Shen, YH |author4=Han, MJ |author5= Zhang, Z |title=The Origin and Evolution of Six Miniature Inverted-Repeat Transposable Elements in Bombyx mori and Rhodnius prolixus|journal=Genome Biology and Evolution|date=January 2013|volume=5|issue=11|pages=2020–31|pmid=24115603|doi=10.1093/gbe/evt153 |pmc=3845634}}</ref> Inverted repeats are principally found at the origins of replication of cell organism and organelles that range from phage plasmids, mitochondria, and eukaryotic viruses to mammalian cells.<ref name=Pearson>{{cite journal|last=Pearson|first=CE|author2=Zorbas, H |author3=Price, GB |author4= Zannis-Hadjopoulos, M |s2cid=22204780|title=Inverted repeats, stem-loops, and cruciforms: significance for initiation of DNA replication|journal=Journal of Cellular Biochemistry|date=October 1996|volume=63|issue=1|pages=1–22|pmid=8891900|doi=10.1002/(SICI)1097-4644(199610)63:1<1::AID-JCB1>3.0.CO;2-3}}</ref> The replication origins of the phage G4 and other related phages comprise a segment of nearly 139 nucleotide bases that include three inverted repeats that are essential for replication priming.<ref name=Pearson />

===In the genome===
To a large extent, portions of nucleotide repeats are quite often observed as part of rare DNA combinations.<ref name=Heringa /> The three main repeats which are largely found in particular DNA constructs include the closely precise homopurine-homopyrimidine inverted repeats, which is otherwise referred to as H palindromes, a common occurrence in triple helical H conformations that may comprise either the TAT or CGC nucleotide triads. The others could be described as long inverted repeats having the tendency to produce hairpins and cruciform, and finally direct tandem repeats, which commonly exist in structures described as slipped-loop, cruciform and left-handed Z-DNA.<ref name=Heringa />

===Common in different organisms===
Past studies suggest that repeats are a common feature of [[eukaryotes]] unlike the [[prokaryotes]] and [[archaea]].<ref name=Heringa>{{cite journal|last=Heringa|first=J|title=Detection of internal repeats: how common are they?|journal=Current Opinion in Structural Biology|date=June 1998|volume=8|issue=3|pages=338–45|pmid=9666330|doi=10.1016/S0959-440X(98)80068-7}}</ref> Other reports suggest that irrespective of the comparative shortage of repeat elements in prokaryotic genomes, they nevertheless contain hundreds or even thousands of large repeats.<ref>{{cite journal|last=Treangen|first=TJ|author2=Abraham, AL |author3=Touchon, M |author4= Rocha, EP |title=Genesis, effects and fates of repeats in prokaryotic genomes|journal=FEMS Microbiology Reviews|date=May 2009|volume=33|issue=3|pages=539–71|pmid=19396957|doi=10.1111/j.1574-6976.2009.00169.x|url=https://academic.oup.com/femsre/article-pdf/33/3/539/18141891/33-3-539.pdf|doi-access=free}}</ref>   Current genomic analysis seem to suggest the existence of a large excess of perfect inverted repeats in many prokaryotic genomes as compared to eukaryotic genomes.<ref name=Ladoukakis>{{cite journal|last=Ladoukakis|first=ED|author2=Eyre-Walker, A|title=The excess of small inverted repeats in prokaryotes|journal=Journal of Molecular Evolution|date=September 2008|volume=67|issue=3|pages=291–300|pmid=18696026|doi=10.1007/s00239-008-9151-z|url=http://www.lifesci.susx.ac.uk/home/Adam_Eyre-Walker/Website/Publications_files/LadoukakisJME08.pdf|bibcode=2008JMolE..67..291L|citeseerx=10.1.1.578.7466|s2cid=29953202}}</ref>

[[File:Pseudoknot-Inverted-Repeats.gif|thumb|500 px| Pseudoknot with four sets of inverted repeats. Inverted repeats 1 and 2 create the stem for stem-loop A and are part of the loop for stem-loop B. Similarly, inverted repeats 3 and 4 form the stem for stem-loop B and are part of the loop for stem-loop A.]]

For quantification and comparison of inverted repeats between several species, namely on archaea, see <ref>{{cite book|last=Hosseini|first=M|author2=Pratas, D |author3=Pinho, AJ |title= 11th International Conference on Practical Applications of Computational Biology & Bioinformatics|chapter=On the Role of Inverted Repeats in DNA Sequence Similarity|series=Advances in Intelligent Systems and Computing|publisher=Springer|volume=616|pages=228–236|date=2017|doi=10.1007/978-3-319-60816-7_28|isbn=978-3-319-60815-0}}</ref>

===Inverted repeats in pseudoknots===
[[Pseudoknot]]s are common structural motifs found in RNA.  They are formed by two nested [[stem-loop]]s such that the stem of one structure is formed from the loop of the other.  There are multiple folding [[topology|topologies]] among pseudoknots and great variation in loop lengths, making them a structurally diverse group.<ref name=Staple>{{cite journal|last=Staple|first=DW|author2=Butcher, SE|title=Pseudoknots: RNA structures with diverse functions.|journal=PLOS Biology|date=June 2005|volume=3|issue=6|pages=e213|pmid=15941360|doi=10.1371/journal.pbio.0030213|pmc=1149493 |doi-access=free }} {{open access}}</ref>

Inverted repeats are a key component of pseudoknots as can be seen in the illustration of a naturally occurring pseudoknot found in the human [[telomerase RNA component]].<ref name=chen-greider>{{cite journal|last=Chen|first=JL|author2=Greider, CW|title=Functional analysis of the pseudoknot structure in human telomerase RNA.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Jun 7, 2005|volume=102|issue=23|pages=8080–5; discussion 8077–9|pmid=15849264|doi=10.1073/pnas.0502259102|pmc=1149427|bibcode=2005PNAS..102.8080C|doi-access=free}}</ref> Four different sets of inverted repeats are involved in this structure.  Sets 1 and 2 are the stem of stem-loop A and are part of the loop for stem-loop B.  Similarly, sets 3 and 4 are the stem for stem-loop B and are part of the loop for stem-loop A.

Pseudoknots play a number of different roles in biology.  The telomerase pseudoknot in the illustration is critical to that enzyme's activity.<ref name=chen-greider />  The [[ribozyme]] for the [[Hepatitis D|''hepatitis delta virus (HDV)'']] folds into a double-pseudoknot structure and self-cleaves its circular genome to produce a single-genome-length RNA.  Pseudoknots also play a role in programmed [[ribosomal frameshift]]ing found in some viruses and required in the replication of [[retroviruses]].<ref name=Staple />{{Clear}}

===In riboswitches===
Inverted repeats play an important role in [[riboswitch]]es, which are RNA regulatory elements that control the expression of genes that produce the mRNA, of which they are part.<ref name="Watson"/>  A simplified example of the [[flavin mononucleotide]] (FMN) riboswitch is shown in the illustration. This riboswitch exists in the [[mRNA]] transcript and has several [[stem-loop]] structures upstream from the [[coding region]].  However, only the key stem-loops are shown in the illustration, which has been greatly simplified to help show the role of the inverted repeats.  There are multiple inverted repeats in this riboswitch as indicated in green (yellow background) and blue (orange background). [[File:Ribo100r.gif|thumb|800 px|left]]
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In the absence of FMN, the Anti-termination structure is the preferred [[Conformation activity relationship|conformation]] for the mRNA transcript. It is created by base-pairing of the inverted repeat region circled in red.  When FMN is present, it may bind to the loop and prevent formation of the Anti-termination structure.  This allows two different sets of inverted repeats to base-pair and form the Termination structure.<ref>{{cite journal|last=Winkler|first=WC|author2=Cohen-Chalamish, S |author3=Breaker, RR |title=An mRNA structure that controls gene expression by binding FMN.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Dec 10, 2002|volume=99|issue=25|pages=15908–13|pmid=12456892|doi=10.1073/pnas.212628899|pmc=138538|bibcode=2002PNAS...9915908W|doi-access=free}}</ref>  The stem-loop on the 3' end is a [[Terminator (genetics)|transcriptional terminator]] because the sequence immediately following it is a string of uracils (U).  If this stem-loop forms (due to the presence of FMN) as the growing RNA strand emerges from the [[RNA polymerase]] complex, it will create enough structural tension to cause the RNA strand to dissociate and thus terminate transcription.  The dissociation occurs easily because the base-pairing between the U's in the RNA and the A's in the template strand are the weakest of all base-pairings.<ref name=Watson />  Thus, at higher concentration levels, FMN down-regulates its own transcription by increasing the formation of the termination structure.

==Mutations and disease==
Inverted repeats are often described as "hotspots" of eukaryotic and prokaryotic genomic instability.<ref name=Voineagu>{{cite journal|last=Mirkin|first=I|author2=Narayanan, V |author3=Lobachev, KS |author4= Mirkin, SM |title=Replication stalling at unstable inverted repeats: interplay between DNA hairpins and fork stabilizing proteins|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Jul 22, 2008|volume=105|issue=29|pages=9936–41|pmid=18632578|bibcode=2008PNAS..105.9936V|doi=10.1073/pnas.0804510105|pmc=2481305|doi-access=free}}</ref> Long inverted repeats are deemed to greatly influence the stability of the genome of various organisms.<ref name=Zhao>{{cite journal|last=Stormo|first=G|author2=Chang, KY |author3=Varley, K |author4= Stormo, GD |title=Evidence for active maintenance of inverted repeat structures identified by a comparative genomic approach|journal=PLOS ONE|date=Feb 28, 2007|volume=2|issue=2|pages=e262|pmid=17327921|bibcode=2007PLoSO...2..262Z|doi=10.1371/journal.pone.0000262|pmc=1803023|editor1-last=Hall|editor1-first=Neil|doi-access=free}} {{open access}}</ref> This is exemplified in ''E. coli'', where genomic sequences with long inverted repeats are seldom replicated, but rather deleted with rapidity.<ref name=Zhao /> Again, the long inverted repeats observed in yeast greatly favor recombination within the same and adjacent chromosomes, resulting in an equally very high rate of deletion.<ref name=Zhao /> Finally, a very high rate of deletion and recombination were also observed in mammalian chromosomes regions with inverted repeats.<ref name=Zhao /> Reported differences in the stability of genomes of interrelated organisms are always an indication of a disparity in inverted repeats.<ref name=Achaz /> The instability results from the tendency of inverted repeats to fold into hairpin- or cruciform-like DNA structures. These special structures can hinder or confuse DNA replication and other genomic activities.<ref name=Voineagu /> Thus, inverted repeats lead to special configurations in both [[RNA]] and [[DNA]] that can ultimately cause [[mutation]]s and [[disease]].<ref name=bissler>{{cite journal|last=Bissler|first=JJ|s2cid=12982|title=DNA inverted repeats and human disease|journal=Frontiers in Bioscience|date=Mar 27, 1998|volume=3|issue=4|pages=d408–18|pmid=9516381|doi=10.2741/a284|url=http://pdfs.semanticscholar.org/b2de/c34e8282e46e9285e5f3f09bc9313cb0d804.pdf|archive-url=https://web.archive.org/web/20190303091110/http://pdfs.semanticscholar.org/b2de/c34e8282e46e9285e5f3f09bc9313cb0d804.pdf|url-status=dead|archive-date=March 3, 2019}}</ref>
[[File:DNA palindrome.svg|thumb|600 px|left|Inverted repeat changing to/from an extruded cruciform. &nbsp; A: Inverted Repeat Sequences; &nbsp; B: Loop; &nbsp; C: Stem with base pairing of the inverted repeat sequences]]
The illustration shows an inverted repeat undergoing cruciform extrusion. DNA in the region of the inverted repeat unwinds and then recombines, forming a four-way junction with two [[stem-loop]] structures. The cruciform structure occurs because the inverted repeat sequences self-pair to each other on their own strand.<ref name=ramreddy>{{cite journal|last=Ramreddy|first=T|author2=Sachidanandam, R |author3=Strick, TR |title=Real-time detection of cruciform extrusion by single-molecule DNA nanomanipulation|journal=Nucleic Acids Research|date=May 2011|volume=39|issue=10|pages=4275–83|pmid=21266478|doi=10.1093/nar/gkr008|pmc=3105387}}</ref>

Extruded cruciforms can lead to [[frameshift mutation]]s when a DNA sequence has inverted repeats in the form of a [[palindromic sequence|palindrome]] combined with regions of [[direct repeat]]s on either side. During [[transcription (genetics)|transcription]], slippage and partial dissociation of the polymerase from the template strand can lead to both [[deletion (genetics)|deletion]] and [[insertion (genetics)|insertion]] mutations.<ref name=bissler />  Deletion occurs when a portion of the unwound [[template strand]] forms a stem-loop that gets "skipped" by the transcription machinery. Insertion occurs when a stem-loop forms in a dissociated portion of the nascent (newly synthesized) strand causing a portion of the template strand to be transcribed twice.<ref name=bissler />
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[[File:Antithrombin-gene-strand-switch.gif|frame|right]]<!--|A strand switch event in antithrombin gene creates a missense mutation (GCA to ACA) while perfecting the inverted repeat in the stem region.-->

=== Antithrombin deficiency from a point mutation ===
Imperfect inverted repeats can lead to [[mutation]]s through intrastrand and interstrand switching.<ref name=bissler />  The [[antithrombin]] III gene's coding region is an example of an imperfect inverted repeat as shown in the figure on the right.
The [[stem-loop]] structure forms with a bump at the bottom because the G and T do not pair up. A strand switch event could result in the G (in the bump) being replaced by an A which removes the "imperfection" in the inverted repeat and provides a stronger stem-loop structure. However, the replacement also creates a [[point mutation]] converting the GCA codon to ACA. If the strand switch event is followed by a second round of [[DNA replication]], the mutation may become fixed in the [[genome]] and lead to disease. Specifically, the [[missense mutation]] would lead to a defective gene and a deficiency in antithrombin which could result in the development of [[venous thromboembolism]] (blood clots within a vein).<ref name=bissler />
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[[File:Collagen-gene-strand-switch.gif|frame|left]]<!--|A strand switch event perfects the inverted repeat with a T-insertion in the stem region of the collagen gene and results in a frameshift mutation.-->

=== Osteogenesis imperfecta from a frameshift mutation ===
Mutations in the [[collagen]] gene can lead to the disease [[Osteogenesis Imperfecta]], which is characterized by brittle bones.<ref name=bissler /> In the illustration, a stem-loop formed from an imperfect inverted repeat is mutated with a thymine (T) nucleotide insertion as a result of an inter- or intrastrand switch. The addition of the T creates a [[base-pairing]] "match up" with the adenine (A) that was previously a "bump" on the left side of the stem. While this addition makes the stem stronger and perfects the inverted repeat, it also creates a [[frameshift mutation]] in the nucleotide sequence which alters the [[reading frame]] and will result in an incorrect expression of the gene.<ref name=bissler />
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==Programs and databases==
The following list provides information and external links to various programs and databases for inverted repeats:
*[https://web.archive.org/web/20131113054733/http://nonb.abcc.ncifcrf.gov/apps/site/default non-B DB] A Database for Integrated Annotations and Analysis of non-B DNA Forming Motifs.<ref name=NONB>{{cite journal|last=Cer|first=RZ |author2=Donohue, DE |author3=Mudunuri, US |author4=Temiz, NA |author5=Loss, MA |author6=Starner, NJ |author7=Halusa, GN |author8=Volfovsky, N |author9=Yi, M |author10=Luke, BT |author11=Bacolla, A |author12=Collins, JR |author13=Stephens, RM|title=Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools|journal=Nucleic Acids Research|date=January 2013|volume=41|issue=Database issue|pages=D94–D100|pmid=23125372|doi=10.1093/nar/gks955|pmc=3531222}}</ref>  This database is provided by The Advanced Biomedical Computing Center (ABCC) at then Frederick National Laboratory for Cancer Research (FNLCR). It covers the [[A-DNA]] and [[Z-DNA]] conformations otherwise known as "non-B DNAs" because they are not the more [[B-DNA|common B-DNA]] form of a right-handed Watson-Crick [[nucleic acid double helix|double-helix]].  These "non-B DNAs" include left-handed Z-DNA, [[Cruciform#Cruciform DNA|cruciform]], [[triple-stranded DNA|triplex]], tetraplex and [[stem-loop|hairpin]] structures.<ref name=NONB /> Searches can be performed on a variety of "repeat types" (including inverted repeats) and on several species.
*[http://tandem.bu.edu/cgi-bin/irdb/irdb.exe Inverted Repeats Database] {{Webarchive|url=https://web.archive.org/web/20200901164938/http://tandem.bu.edu/cgi-bin/irdb/irdb.exe |date=2020-09-01 }} Boston University. This database is a web application that allows query and analysis of repeats held in the PUBLIC DATABASE project. Scientists can also analyze their own sequences with the Inverted Repeats Finder algorithm.<ref>{{cite journal|last=Gelfand|first=Y|author2=Rodriguez, A |author3=Benson, G |title=TRDB--the Tandem Repeats Database|journal=Nucleic Acids Research|date=January 2007|volume=35|issue=Database issue|pages=D80–7|pmid=17175540|doi=10.1093/nar/gkl1013|pmc=1781109}}</ref>
*[http://pmite.hzau.edu.cn/django/mite/ P-MITE: a Plant MITE database] &mdash;  this database for [[Miniature Inverted-repeat Transposable Elements]] (MITEs) contains sequences from [[Plant genomes#Plants|plant genomes]]. Sequences may be searched or downloaded from the database.<ref>{{cite journal|last=Chen|first=J|author2=Hu, Q |author3=Zhang, Y |author4=Lu, C |author5= Kuang, H |title=P-MITE: a database for plant miniature inverted-repeat transposable elements|journal=Nucleic Acids Research|date=Oct 29, 2013|pmid=24174541|doi=10.1093/nar/gkt1000|volume=42|issue=1|pages=D1176–81 |pmc=3964958}}</ref> 
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*[http://www.cbs.dtu.dk/services/GenomeAtlas/ Genome Atlas Database] — contains hundreds of examples
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*[[EMBOSS]] is the "European Molecular Biology Open Software Suite" which runs on [[UNIX]] and [[UNIX-like]] operating systems.<ref name=EMBOSS>{{cite journal|last=Rice|first=P|author2=Longden, I |author3=Bleasby, A |title=EMBOSS: the European Molecular Biology Open Software Suite|journal=Trends in Genetics|date=June 2000|volume=16|issue=6|pages=276–7|pmid=10827456|url=http://emboss.sourceforge.net/index.html|doi=10.1016/S0168-9525(00)02024-2|url-access=subscription}}</ref> Documentation and program source files are available on the [http://emboss.sourceforge.net/news/ EMBOSS website].  Applications specifically related to inverted repeats are listed below:
**[http://emboss.sourceforge.net/apps/cvs/emboss/apps/einverted.html EMBOSS einverted]: Finds inverted repeats in [[nucleic acid sequence|nucleotide sequences]]. Threshold values can be set to limit the scope of the search.<ref name=EMBOSS /> 
**[http://emboss.sourceforge.net/apps/cvs/emboss/apps/palindrome.html EMBOSS palindrome]: Finds [[palindromic sequence|palindromes]] such as [[stem-loop|stem loop]] regions in nucleotide sequences. The program will find sequences that include sections of mismatches and gaps that may correspond to bulges in a stem loop.<ref name=EMBOSS />

==References==
{{reflist|2}}

== External links ==
* {{MeshName|Inverted+Repeat+Sequence}}

{{Repeated sequence}}

[[Category:Repetitive DNA sequences]]
[[Category:Molecular biology]]