Editing Inverted repeat (section)

==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 />
{{Clear}}
[[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 />
{{Clear}}
[[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 />
{{Clear}}