Editing Chromosomal crossover (section)

==Non-homologous crossover==
{{See also|Unequal crossing over|Chromosomal translocation}}

Crossovers typically occur between [[Sequence homology|homologous regions]] of matching [[chromosome]]s, but similarities in sequence and other factors can result in mismatched alignments. Most DNA is composed of [[base pair]] sequences repeated very large numbers of times.<ref name="Smith 528–535">{{cite journal | vauthors = Smith GP | title = Evolution of repeated DNA sequences by unequal crossover | journal = Science | volume = 191 | issue = 4227 | pages = 528–535 | date = February 1976 | pmid = 1251186 | doi = 10.1126/science.1251186 | bibcode = 1976Sci...191..528S | jstor = 1741301 }}</ref> These repetitious segments, often referred to as satellites, are fairly homogeneous among a species.<ref name="Smith 528–535"/> During [[DNA replication]], each strand of DNA is used as a template for the creation of new strands using a partially-conserved mechanism; proper functioning of this process results in two identical, paired chromosomes, often called sisters. [[Sister chromatids|Sister chromatid]] crossover events are known to occur at a rate of several crossover events per cell per division in [[eukaryote]]s.<ref name="Smith 528–535"/> Most of these events involve an exchange of equal amounts of genetic information, but unequal exchanges may occur due to sequence mismatch. These are referred to by a variety of names, including non-homologous crossover, unequal crossover, and unbalanced recombination, and result in an [[Insertion (genetics)|insertion]] or [[Deletion (genetics)|deletion]] of genetic information into the chromosome. While rare compared to homologous crossover events, these mutations are drastic, affecting many [[locus (genetics)|loci]] at the same time. They are considered the main driver behind the generation of [[gene duplication]]s and are a general source of [[mutation]] within the [[genome]].<ref>{{Cite book |url=https://books.google.com/books?id=Bf5-QgAACAAJ |title=Fundamentals of Molecular Evolution | vauthors = Graur D, Li WH |date=2000 |publisher=Sinauer |isbn=9780878932665 |language=en}}</ref>

The specific causes of non-homologous crossover events are unknown, but several influential factors are known to increase the likelihood of an unequal crossover. One common vector leading to unbalanced recombination is the repair of [[DNA repair|double-strand breaks]].<ref name="Puchta 1–14">{{cite journal | vauthors = Puchta H | title = The repair of double-strand breaks in plants: mechanisms and consequences for genome evolution | journal = Journal of Experimental Botany | volume = 56 | issue = 409 | pages = 1–14 | date = January 2005 | pmid = 15557293 | doi = 10.1093/jxb/eri025 | doi-access = free }}</ref> Double-stranded DNA breaks are often repaired using homology directed repair, a process which involves invasion of a [[template strand]] by the double-stranded DNA break strand (see figure below). Nearby homologous regions of the template strand are often used for repair, which can give rise to either insertions or deletions in the genome if a non-homologous but [[Complementary DNA|complementary]] part of the template strand is used.<ref name="Puchta 1–14"/> Sequence similarity is a major player in crossover – crossover events are more likely to occur in long regions of close identity on a gene.<ref>{{cite journal | vauthors = Metzenberg AB, Wurzer G, Huisman TH, Smithies O | title = Homology requirements for unequal crossing over in humans | journal = Genetics | volume = 128 | issue = 1 | pages = 143–161 | date = May 1991 | pmid = 2060774 | pmc = 1204444 | doi = 10.1093/genetics/128.1.143 }}</ref> This means that any section of the genome with long sections of repetitive DNA is prone to crossover events.{{cn|date=December 2024}}

The presence of [[transposable element]]s is another influential element of non-homologous crossover. Repetitive regions of code characterize transposable elements; complementary but non-homologous regions are ubiquitous within transposons. Because chromosomal regions composed of transposons have large quantities of identical, repetitious code in a condensed space, it is thought that transposon regions undergoing a crossover event are more prone to erroneous complementary match-up;<ref>{{cite journal | vauthors = Robberecht C, Voet T, Zamani Esteki M, Nowakowska BA, Vermeesch JR | title = Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations | journal = Genome Research | volume = 23 | issue = 3 | pages = 411–418 | date = March 2013 | pmid = 23212949 | pmc = 3589530 | doi = 10.1101/gr.145631.112 }}</ref> that is to say, a section of a chromosome containing a lot of identical sequences, should it undergo a crossover event, is less certain to match up with a perfectly homologous section of complementary code and more prone to binding with a section of code on a slightly different part of the chromosome. This results in unbalanced recombination, as genetic information may be either inserted or deleted into the new chromosome, depending on where the recombination occurred.{{cn|date=December 2024}}

While the motivating factors behind unequal recombination remain obscure, elements of the physical mechanism have been elucidated. [[Mismatch repair]] (MMR) proteins, for instance, are a well-known regulatory family of proteins, responsible for regulating mismatched sequences of DNA during replication and escape regulation.<ref name="Kunkel 681–710">{{cite journal | vauthors = Kunkel TA, Erie DA | title = DNA mismatch repair | journal = Annual Review of Biochemistry | volume = 74 | issue = 1 | pages = 681–710 | date = 2005 | pmid = 15952900 | doi = 10.1146/annurev.biochem.74.082803.133243 | url = https://zenodo.org/record/1234939 }}</ref> The operative goal of MMRs is the restoration of the parental genotype. One class of MMR in particular, MutSβ, is known to initiate the correction of insertion-deletion mismatches of up to 16 nucleotides.<ref name="Kunkel 681–710"/> Little is known about the excision process in eukaryotes, but ''E. coli'' excisions involve the cleaving of a nick on either the 5' or 3' strand, after which [[DNA helicase]] and [[DNA polymerase III holoenzyme|DNA polymerase]] III bind and generate single-stranded proteins, which are digested by [[exonuclease]]s and attached to the strand by [[ligase]].<ref name="Kunkel 681–710"/> Multiple MMR pathways have been implicated in the maintenance of complex organism genome stability, and any of many possible malfunctions in the MMR pathway result in DNA editing and correction errors.<ref>{{cite journal | vauthors = Surtees JA, Argueso JL, Alani E | title = Mismatch repair proteins: key regulators of genetic recombination | journal = Cytogenetic and Genome Research | volume = 107 | issue = 3–4 | pages = 146–159 | date = 2004 | pmid = 15467360 | doi = 10.1159/000080593 | s2cid = 19219813 }}</ref> Therefore, while it is not certain precisely what mechanisms lead to errors of non-homologous crossover, it is extremely likely that the MMR pathway is involved.{{cn|date=December 2024}}