Editing Chromosomal crossover

{{Short description|Cellular process}}
{{Use dmy dates|date=April 2017}}
[[File:Chromosomal Crossover.svg|thumb|upright=1.15|Crossing over occurs between prophase I and metaphase I and is the process where two homologous non-sister chromatids pair up with each other and exchange different segments of genetic material to form two recombinant chromosome sister chromatids. It can also happen during mitotic division,<ref>{{cite book |vauthors = Griffiths AJ, Gelbart WM, Miller JH |display-authors=etal |title=Modern Genetic Analysis | chapter = Mitotic Crossing-Over  | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK21438/ |place=New York |publisher=W. H. Freeman |date=1999}}</ref> which may result in loss of heterozygosity. Crossing over is important for the normal segregation of chromosomes during meiosis.<ref>{{cite journal | vauthors = Wang S, Zickler D, Kleckner N, Zhang L | title = Meiotic crossover patterns: obligatory crossover, interference and homeostasis in a single process | journal = Cell Cycle | volume = 14 | issue = 3 | pages = 305–314 | date = 2015-02-01 | pmid = 25590558 | pmc = 4353236 | doi = 10.4161/15384101.2014.991185 }}</ref> Crossing over also accounts for genetic variation, because due to the swapping of genetic material during crossing over, the [[chromatid]]s held together by the [[centromere]] are no longer identical. So, when the chromosomes go on to meiosis II and separate, some of the daughter cells receive daughter chromosomes with recombined alleles. Due to this genetic recombination, the offspring have a different set of alleles and genes than their parents do. In the diagram, genes B and b are crossed over with each other, making the resulting recombinants after meiosis Ab, AB, ab, and aB.]]
[[Image:Morgan crossover 1.jpg|thumb|Thomas Hunt Morgan's illustration of crossing over (1916)]]
[[Image:Morgan crossover 2.jpg|thumb|A double crossing over]]

'''Chromosomal crossover''', or '''crossing over''', is the exchange of genetic material during [[sexual reproduction]] between two [[homologous chromosome]]s' [[sister chromatids|non-sister chromatids]] that results in recombinant [[chromosome]]s. It is one of the final phases of [[genetic recombination]], which occurs in the ''pachytene'' stage of [[prophase I]] of [[meiosis]] during a process called [[synapsis]]. Synapsis is usually initiated before the [[synaptonemal complex]] develops and is not completed until near the end of prophase&nbsp;I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome, resulting in [[Chiasma (genetics)|chiasma]] which are the visible evidence of crossing over. 

== History of discovery ==
Crossing over was described, in theory, by [[Thomas Hunt Morgan]]; the term crossover was coined by Morgan and Eleth Cattell.<ref>{{Cite journal | vauthors = Morgan TH, Cattell E |date=1912 |title=Data for the study of sex-linked inheritance in Drosophila |journal=Journal of Experimental Zoology | issue = 1 |volume=13  |pages=79–101|doi=10.1002/jez.1400130105 |bibcode=1912JEZ....13...79M |url=https://zenodo.org/record/2153714 }}</ref> Hunt relied on the discovery of [[Frans Alfons Janssens]] who described the phenomenon in 1909 and had called it "chiasmatypie".<ref>{{cite journal | vauthors = Janssens FA, Koszul R, Zickler D | title = The chiasmatype theory. A new interpretation of the maturation divisions. 1909 | journal = Genetics | volume = 191 | issue = 2 | pages = 319–346 | date = June 2012 | pmid = 22701051 | pmc = 3374304 | doi = 10.1534/genetics.112.139725 }}</ref> The term ''[[chiasma (genetics)|chiasma]]'' is linked, if not identical, to chromosomal crossover. Morgan immediately saw the great importance of Janssens' cytological interpretation of chiasmata to the experimental results of his research on the heredity of ''[[Drosophila]]''. The physical basis of crossing over was first demonstrated by [[Harriet Creighton]] and [[Barbara McClintock]] in 1931.<ref>{{cite journal | vauthors = Creighton HB, McClintock B | title = A Correlation of Cytological and Genetical Crossing-Over in Zea Mays | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 17 | issue = 8 | pages = 492–497 | date = August 1931 | pmid = 16587654 | pmc = 1076098 | doi = 10.1073/pnas.17.8.492 | doi-access = free | bibcode = 1931PNAS...17..492C }} (Original paper)</ref>

The linked frequency of crossing over between two [[gene]] loci ([[genetic marker|markers]]) is the ''[[crossing-over value]]''. For fixed set of genetic and environmental conditions, [[genetic recombination|recombination]] in a particular region of a linkage structure ([[chromosome]]) tends to be constant and the same is then true for the crossing-over value which is used in the production of [[genetic map]]s.<ref name="RM">{{cite book | vauthors = Rieger R, Michaelis A, Green MM |year=1976 |title=Glossary of genetics and cytogenetics: Classical and molecular |publisher=Springer-Verlag |place=Heidelberg – New York |isbn=978-3-540-07668-1}}</ref><ref>{{cite book | vauthors = King RC, Stransfield WD |year=1998 |title=Dictionary of genetics |publisher=Oxford University Press |place=New York & Oxford |isbn=0-19-50944-1-7}} {{ISBN|0-19-509442-5}}.</ref>

When Hotta et al. in 1977 compared [[meiosis|meiotic]] crossing-over ([[genetic recombination|recombination]]) in lily and mouse they concluded that diverse [[eukaryote]]s share a common pattern.<ref>{{cite journal | vauthors = Hotta Y, Chandley AC, Stern H | title = Meiotic crossing-over in lily and mouse | journal = Nature | volume = 269 | issue = 5625 | pages = 240–242 | date = September 1977 | pmid = 593319 | doi = 10.1038/269240a0 | s2cid = 4268089 | bibcode = 1977Natur.269..240H }}</ref> This finding suggested that chromosomal crossing over is a general characteristic of eukaryotic meiosis.

==Origins==
There are two popular and overlapping theories that explain the origins of crossing-over, coming from the different theories on the origin of [[meiosis]]. The first theory rests upon the idea that meiosis evolved as another method of [[DNA repair]], and thus crossing-over is a novel way to replace possibly damaged sections of DNA.<ref name="ReferenceA"/> The second theory comes from the idea that meiosis evolved from [[bacterial transformation]], with the function of propagating diversity.<ref name="ReferenceA">{{cite journal |vauthors=Bernstein H, Bernstein C |title=Evolutionary origin of recombination during meiosis |journal=BioScience |date=2010 |volume=60 |issue=7 |pages=498–505 |doi=10.1525/bio.2010.60.7.5 |s2cid=86663600}}<!--|access-date=10 March 2015--></ref>

In 1931, Barbara McClintock discovered a triploid maize plant. She made key findings regarding corn's karyotype, including the size and shape of the chromosomes. McClintock used the prophase and metaphase stages of mitosis to describe the morphology of corn's chromosomes, and later showed the first ever cytological demonstration of crossing over in meiosis. Working with student Harriet Creighton, McClintock also made significant contributions to the early understanding of codependency of linked genes.{{cn|date=December 2024}}

===DNA repair theory===
Crossing over and DNA repair are very similar processes, which utilize many of the same protein complexes.<ref>{{cite journal | vauthors = Dangel NJ, Knoll A, Puchta H | title = MHF1 plays Fanconi anaemia complementation group M protein (FANCM)-dependent and FANCM-independent roles in DNA repair and homologous recombination in plants | journal = The Plant Journal | volume = 78 | issue = 5 | pages = 822–833 | date = June 2014 | pmid = 24635147 | doi = 10.1111/tpj.12507 | doi-access = free | bibcode = 2014PlJ....78..822D }}</ref><ref>{{cite journal | vauthors = Saponaro M, Callahan D, Zheng X, Krejci L, Haber JE, Klein HL, Liberi G | title = Cdk1 targets Srs2 to complete synthesis-dependent strand annealing and to promote recombinational repair | journal = PLOS Genetics | volume = 6 | issue = 2 | pages = e1000858 | date = February 2010 | pmid = 20195513 | pmc = 2829061 | doi = 10.1371/journal.pgen.1000858 | doi-access = free }}</ref>
In her report, "The Significance of Responses of the Genome to Challenge", McClintock studied corn to show how corn's genome would change itself to overcome threats to its survival. She used 450 self-pollinated plants that received from each parent a chromosome with a ruptured end. She used modified patterns of gene expression on different sectors of leaves of her corn plants to show that transposable elements ("controlling elements") hide in the genome, and their mobility allows them to alter the action of genes at different loci. These elements can also restructure the genome, anywhere from a few nucleotides to whole segments of chromosome.
Recombinases and primases lay a foundation of nucleotides along the DNA sequence. One such particular protein complex that is conserved between processes is [[RAD51]], a well conserved recombinase protein that has been shown to be crucial in DNA repair as well as cross over.<ref>{{cite journal | vauthors = Esposito MS | title = Evidence that spontaneous mitotic recombination occurs at the two-strand stage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 75 | issue = 9 | pages = 4436–4440 | date = September 1978 | pmid = 360220 | pmc = 336130 | doi = 10.1073/pnas.75.9.4436 | doi-access = free | bibcode = 1978PNAS...75.4436E }}<!--|access-date=20 March 2015--></ref> 

Several other genes in ''D. melanogaster'' have been linked as well to both processes, by showing that mutants at these specific loci cannot undergo DNA repair or crossing over. Such genes include mei-41, mei-9, hdm, {{not a typo|spnA}}, and brca2.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}  This large group of conserved genes between processes supports the theory of a close evolutionary relationship.
Furthermore, DNA repair and crossover have been found to favor similar regions on chromosomes. In an experiment using [[radiation hybrid mapping]] on wheat's (''Triticum aestivum L.'') 3B chromosome, crossing over and DNA repair were found to occur predominantly in the same regions.<ref>{{cite journal | vauthors = Kumar A, Bassi FM, Paux E, Al-Azzam O, de Jimenez MM, Denton AM, Gu YQ, Huttner E, Kilian A, Kumar S, Goyal A, Iqbal MJ, Tiwari VK, Dogramaci M, Balyan HS, Dhaliwal HS, Gupta PK, Randhawa GS, Feuillet C, Pawlowski WP, Kianian SF | display-authors = 6 | title = DNA repair and crossing over favor similar chromosome regions as discovered in radiation hybrid of Triticum | journal = BMC Genomics | volume = 13 | issue = 339 | pages = 339 | date = July 2012 | pmid = 22827734 | pmc = 3443642 | doi = 10.1186/1471-2164-13-339 | doi-access = free }}</ref> Furthermore, crossing over has been correlated to occur in response to stressful, and likely DNA damaging, conditions.<ref>{{cite journal | vauthors = Steinboeck F, Hubmann M, Bogusch A, Dorninger P, Lengheimer T, Heidenreich E | title = The relevance of oxidative stress and cytotoxic DNA lesions for spontaneous mutagenesis in non-replicating yeast cells | journal = Mutation Research | volume = 688 | issue = 1–2 | pages = 47–52 | date = June 2010 | pmid = 20223252 | doi = 10.1016/j.mrfmmm.2010.03.006 | bibcode = 2010MRFMM.688...47S }}<!--|access-date=14 March 2015--></ref><ref>{{cite journal | vauthors = Nedelcu AM, Marcu O, Michod RE | title = Sex as a response to oxidative stress: a twofold increase in cellular reactive oxygen species activates sex genes | journal = Proceedings. Biological Sciences | volume = 271 | issue = 1548 | pages = 1591–1596 | date = August 2004 | pmid = 15306305 | pmc = 1691771 | doi = 10.1098/rspb.2004.2747 }}</ref>

===Links to bacterial transformation===
The process of bacterial transformation also shares many similarities with chromosomal cross over, particularly in the formation of overhangs on the sides of the broken DNA strand, allowing for the annealing of a new strand. Bacterial transformation itself has been linked to DNA repair many times.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}  The second theory comes from the idea that meiosis evolved from [[bacterial transformation]], with the function of propagating genetic diversity.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Charpentier X, Kay E, Schneider D, Shuman HA | title = Antibiotics and UV radiation induce competence for natural transformation in Legionella pneumophila | journal = Journal of Bacteriology | volume = 193 | issue = 5 | pages = 1114–1121 | date = March 2011 | pmid = 21169481 | pmc = 3067580 | doi = 10.1128/JB.01146-10 }}</ref>  Thus, this evidence suggests that it is a question of whether cross over is linked to DNA repair or bacterial transformation, as the two do not appear to be mutually exclusive. It is likely that crossing over may have evolved from bacterial transformation, which in turn developed from DNA repair, thus explaining the links between all three processes. {{cn|date=December 2024}}

== Biochemistry of meiotic recombination ==
[[File:Homologous Recombination.jpg|thumb|upright=1.35|A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with a homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.]]

Meiotic recombination may be initiated by double-stranded breaks that are introduced into the DNA by exposure to DNA damaging agents,<ref name="ReferenceA"/> or the [[Spo11]] protein.<ref>{{cite journal | vauthors = Keeney S, Giroux CN, Kleckner N | title = Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family | journal = Cell | volume = 88 | issue = 3 | pages = 375–384 | date = February 1997 | pmid = 9039264 | doi = 10.1016/S0092-8674(00)81876-0 | s2cid = 8294596 | doi-access = free }}</ref> One or more [[exonuclease]]s then digest the [[Directionality (molecular biology)|5' ends]] generated by the double-stranded breaks to produce 3' single-stranded DNA tails (see diagram). The meiosis-specific [[recombinase]] [[Dmc1]] and the general recombinase [[Rad51]] coat the single-stranded DNA to form nucleoprotein filaments.<ref>{{cite journal | vauthors = Sauvageau S, Stasiak AZ, Banville I, Ploquin M, Stasiak A, Masson JY | title = Fission yeast rad51 and dmc1, two efficient DNA recombinases forming helical nucleoprotein filaments | journal = Molecular and Cellular Biology | volume = 25 | issue = 11 | pages = 4377–4387 | date = June 2005 | pmid = 15899844 | pmc = 1140613 | doi = 10.1128/MCB.25.11.4377-4387.2005 }}</ref> The recombinases catalyze invasion of the opposite [[chromatid]] by the single-stranded DNA from one end of the break. Next, the 3' end of the invading DNA primes DNA synthesis, causing displacement of the complementary strand, which subsequently anneals to the single-stranded DNA generated from the other end of the initial double-stranded break. The structure that results is a ''cross-strand exchange'', also known as a [[Holliday junction]]. The contact between two chromatids that will soon undergo crossing-over is known as a ''[[chiasma (genetics)|chiasma]]''. The Holliday junction is a [[Tetrahedron|tetrahedral]] structure which can be 'pulled' by other recombinases, moving it along the four-stranded structure.{{cn|date=December 2024}}
{{gallery |mode=packed
|width=160 |height=160
|Image:Holliday Junction.svg|Holliday Junction
|Image:Holliday junction.jpg|Molecular structure of a Holliday junction.
|Image:Holliday junction coloured.png|Molecular structure of a Holliday junction. From {{PDB|3CRX}}.
}}

===MSH4 and MSH5===
The MSH4 and MSH5 proteins form a hetero-oligomeric structure ([[Protein dimer|heterodimer]]) in yeast and humans.<ref name=Pochart>{{cite journal | vauthors = Pochart P, Woltering D, Hollingsworth NM | title = Conserved properties between functionally distinct MutS homologs in yeast | journal = The Journal of Biological Chemistry | volume = 272 | issue = 48 | pages = 30345–30349 | date = November 1997 | pmid = 9374523 | doi = 10.1074/jbc.272.48.30345 | doi-access = free }}</ref><ref name="pmid9787078">{{cite journal | vauthors = Winand NJ, Panzer JA, Kolodner RD | title = Cloning and characterization of the human and Caenorhabditis elegans homologs of the Saccharomyces cerevisiae MSH5 gene | journal = Genomics | volume = 53 | issue = 1 | pages = 69–80 | date = October 1998 | pmid = 9787078 | doi = 10.1006/geno.1998.5447 | doi-access = free }}</ref><ref name="pmid10029069">{{cite journal | vauthors = Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R | display-authors = 6 | title = hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis | journal = Cancer Research | volume = 59 | issue = 4 | pages = 816–822 | date = February 1999 | pmid = 10029069 }}</ref>  In the yeast ''[[Saccharomyces cerevisiae]]'', MSH4 and MSH5 act specifically to facilitate crossovers between [[homologous chromosome]]s during [[meiosis]].<ref name=Pochart />  The MSH4/MSH5 complex binds and stabilizes double [[Holliday junction]]s and promotes their resolution into crossover products.  An MSH4 [[Muller's morphs#Hypomorph|hypomorphic]] (partially functional) mutant of ''S. cerevisiae'' showed a 30% genome-wide reduction in crossover numbers and a large number of [[Meiosis|meioses]] with non-exchange chromosomes.<ref name="pmid25467183">{{cite journal | vauthors = Krishnaprasad GN, Anand MT, Lin G, Tekkedil MM, Steinmetz LM, Nishant KT | title = Variation in crossover frequencies perturb crossover assurance without affecting meiotic chromosome segregation in Saccharomyces cerevisiae | journal = Genetics | volume = 199 | issue = 2 | pages = 399–412 | date = February 2015 | pmid = 25467183 | pmc = 4317650 | doi = 10.1534/genetics.114.172320 }}</ref>  Nevertheless, this [[mutant]] gave rise to [[spore]] viability patterns suggesting that [[Chromosome segregation|segregation]] of non-exchange chromosomes occurred efficiently.  Thus in ''S. cerevisiae'' proper segregation apparently does not entirely depend on crossovers between [[Homologous chromosome|homologous]] pairs.{{cn|date=December 2024}} In humans, biallelic loss of function variants to MSH4 and MSH5 are compatible with life, but are associated with azospermia in males (spermatogenic failure) and premature ovarian failure in females.<ref>{{cite web |url=https://www.omim.org/entry/602105 |title=Entry - *602105 - MutS HOMOLOG 4; MSH4 - OMIM }}</ref><ref>{{cite web |url=https://www.omim.org/entry/603382?search=msh5&highlight=msh5 | title=Entry - *603382 - MutS HOMOLOG 5; MSH5 - OMIM }}</ref>
[[File:Meiosis crossover.png|thumb|Chiasma is the point of crossing over of the arms of sister chromatids.  ]]

===Chiasma===
Chiasma (plural: chiasmata) are essential for the correct alignment and segregation of homologous chromosomes at meiosis I, and their frequency reflects the rate of genetic recombination, which contributes to variation among offspring. Chiasma number tends to increase with genome size, as larger genomes generally undergo more crossover events per meiosis.<ref>{{Cite journal |last=Ross-Ibarra |first=J. |date=March 2007 |title=Genome size and recombination in angiosperms: a second look |url=https://academic.oup.com/jeb/article/20/2/800-806/7324572 |journal=Journal of Evolutionary Biology |language=en |volume=20 |issue=2 |pages=800–806 |doi=10.1111/j.1420-9101.2006.01275.x |pmid=17305845 |issn=1010-061X}}</ref> Each homologous pair forms a [[Bivalent (genetics)|bivalent]] (or tetrad), consisting of four chromatids. The number and position of chiasmata influence the shape of bivalents, rod-shaped with one chiasma and ring-shaped with two or more.<ref>{{Cite journal |last1=López |first1=E. |last2=Pradillo |first2=M. |last3=Oliver |first3=C. |last4=Romero |first4=C. |last5=Cuñado |first5=N. |last6=Santos |first6=J. L. |date=January 2012 |title=Looking for natural variation in chiasma frequency in Arabidopsis thaliana |url=https://academic.oup.com/jxb/article-lookup/doi/10.1093/jxb/err319 |journal=Journal of Experimental Botany |language=en |volume=63 |issue=2 |pages=887–894 |doi=10.1093/jxb/err319 |issn=1460-2431}}</ref><ref>{{Cite journal |last1=Zickler |first1=Denise |last2=Kleckner |first2=Nancy |date=2015-05-18 |title=Recombination, Pairing, and Synapsis of Homologs during Meiosis |url=https://doi.org/10.1101/cshperspect.a016626 |journal=Cold Spring Harbor Perspectives in Biology |volume=7 |issue=6 |pages=a016626 |doi=10.1101/cshperspect.a016626 |pmid=25986558 |issn=1943-0264|pmc=4448610 }}</ref> 

The grasshopper ''[[Melanoplus femurrubrum|Melanoplus femur-rubrum]]'' was exposed to an acute dose of [[X-ray]]s during each individual stage of [[meiosis]], and [[Chiasma (genetics)|chiasma]] frequency was measured.<ref name="pmid5797806">{{cite journal | vauthors = Church K, Wimber DE | title = Meiosis in the grasshopper: chiasma frequency after elevated temperature and x-rays | journal = Canadian Journal of Genetics and Cytology | volume = 11 | issue = 1 | pages = 209–216 | date = March 1969 | pmid = 5797806 | doi = 10.1139/g69-025 }}</ref>  Irradiation during the [[Leptotene stage|leptotene]]-[[Meiosis#zygotene|zygotene]] stages of [[meiosis]] (that is, prior to the [[Meiosis#Pachytene|pachytene]] period in which crossover recombination occurs) was found to increase subsequent chiasma frequency.  Similarly, in the grasshopper ''[[Chorthippus brunneus]]'', exposure to X-irradiation during the zygotene-early pachytene stages caused a significant increase in mean cell chiasma frequency.<ref name="pmid5289295">{{cite journal | vauthors = Westerman M | title = The effect of x-irradiation on chiasma frequency in Chorthippus brunneus | journal = Heredity | volume = 27 | issue = 1 | pages = 83–91 | date = August 1971 | pmid = 5289295 | doi = 10.1038/hdy.1971.73 | doi-access = free | bibcode = 1971Hered..27...83W }}</ref>  Chiasma frequency was scored at the later [[Meiosis#diplotene|diplotene-diakinesis]] stages of meiosis.  These results show that [[Ionizing radiation|ionising-radiation]] induced [[DNA repair|double-stranded DNA breaks]] were subsequently repaired by a crossover pathway leading to chiasma formation.<ref>{{Cite journal |last1=Szostak |first1=Jack W. |last2=Orr-Weaver |first2=Terry L. |last3=Rothstein |first3=Rodney J. |last4=Stahl |first4=Franklin W. |date=May 1983 |title=The double-strand-break repair model for recombination |url=https://linkinghub.elsevier.com/retrieve/pii/0092867483903318 |journal=Cell |language=en |volume=33 |issue=1 |pages=25–35 |doi=10.1016/0092-8674(83)90331-8}}</ref>

However, increased crossover frequency following radiation-induced DNA damage does not universally occur in all insects; for example, ''Drosophila'' females exhibit predominantly non-crossover repair pathways when responding to induced double-stranded DNA breaks, resulting in a relatively low ratio of crossovers to non-crossovers.<ref>{{Cite journal |last1=Mehrotra |first1=S. |last2=McKim |first2=K. S. |date=2006 |title=Temporal Analysis of Meiotic DNA Double-Strand Break Formation and Repair in Drosophila Females |journal=PLOS Genetics |language=en |volume=2 |issue=11 |pages=e200 |doi=10.1371/journal.pgen.0020200 |doi-access=free |issn=1553-7390 |pmc=1657055 |pmid=17166055}}</ref>

===Class I and class II crossovers===
Double-strand breaks are repaired by two pathways to generate crossovers in eukaryotes.<ref>{{cite journal | vauthors = Holloway JK, Booth J, Edelmann W, McGowan CH, Cohen PE | title = MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis | journal = PLOS Genetics | volume = 4 | issue = 9 | pages = e1000186 | date = September 2008 | pmid = 18787696 | pmc = 2525838 | doi = 10.1371/journal.pgen.1000186 | doi-access = free }}</ref> The majority of them are repaired by MutL homologs MLH1 and MLH3, which defines the class I crossovers. The remaining are the result of the class II pathway, which is regulated by MUS81 endonuclease and [[FANCM]] translocase. There are interconnections between these two pathways—class I crossovers can compensate for the loss of class II pathway. In MUS81 knockout mice, class I crossovers are elevated, while total crossover counts at chiasmata are normal. However, the mechanisms underlining this crosstalk are not well understood. A recent study suggests that a scaffold protein called SLX4 may participate in this regulation.<ref>{{cite journal | vauthors = Holloway JK, Mohan S, Balmus G, Sun X, Modzelewski A, Borst PL, Freire R, Weiss RS, Cohen PE | display-authors = 6 | title = Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis | journal = PLOS Genetics | volume = 7 | issue = 6 | pages = e1002094 | date = June 2011 | pmid = 21655083 | pmc = 3107204 | doi = 10.1371/journal.pgen.1002094 | doi-access = free }}</ref> Specifically, SLX4 knockout mice largely phenocopies the MUS81 knockout—once again, an elevated class I crossovers while normal chiasmata count. In FANCM knockout mice, the class II pathway is hyperactivated, resulting in increased numbers of crossovers that are independent of the MLH1/MLH3 pathway.<ref>{{cite journal | vauthors = Tsui V, Lyu R, Novakovic S, Stringer JM, Dunleavy JE, Granger E, Semple T, Leichter A, Martelotto LG, Merriner DJ, Liu R, McNeill L, Zerafa N, Hoffmann ER, O'Bryan MK, Hutt K, Deans AJ, Heierhorst J, McCarthy DJ, Crismani W | display-authors = 6 | title = ''Fancm'' has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals | journal = Cell Genomics | volume = 3 | issue = 8 | pages = 100349 | date = August 2023 | pmid = 37601968 | pmc = 10435384 | doi = 10.1016/j.xgen.2023.100349 }}</ref>

==Consequences==
[[Image:Conversion and crossover.jpg|thumb|right |upright=1.15|The difference between [[gene conversion]] and chromosomal crossover.]]
In most [[eukaryote]]s, a [[cell (biology)|cell]] carries two versions of each [[gene]], each referred to as an [[allele]]. Each parent passes on one allele to each offspring. An individual [[gamete]] inherits a complete haploid complement of alleles on chromosomes that are independently selected from each pair of [[chromatid]]s lined up on the metaphase plate. Without recombination, all alleles for those genes linked together on the same chromosome would be inherited together. [[Meiotic non-disjunction|Meiotic]] recombination allows a more independent [[Segregation (materials science)|segregation]] between the two alleles that occupy the positions of single genes, as recombination shuffles the allele content between homologous chromosomes.{{cn|date=December 2024}}

Recombination results in a new arrangement of maternal and paternal alleles on the same chromosome. Although the same genes appear in the same order, some alleles are different. In this way, it is theoretically possible to have any combination of parental alleles in an offspring, and the fact that two alleles appear together in one offspring does not have any influence on the [[Statistical hypothesis testing|statistical]] [[probability]] that another offspring will have the same combination. This principle of "[[Mendelian inheritance|independent assortment]]" of genes is fundamental to genetic inheritance.<ref name = "Darling">{{cite web |url=http://www.daviddarling.info/encyclopedia/G/genetic_recombination.html |title=Genetic recombination | vauthors = Darling D }}</ref>
However, the frequency of recombination is actually not the same for all gene combinations. This leads to the notion of "[[centiMorgan|genetic distance]]", which is a measure of recombination [[frequency]] averaged over a (suitably large) sample of [[Genealogy|pedigrees.]] Loosely speaking, one may say that this is because recombination is greatly influenced by the proximity of one gene to another. If two genes are located close together on a chromosome, the likelihood that a recombination event will separate these two genes is less than if they were farther apart. [[Genetic linkage]] describes the tendency of genes to be inherited together as a result of their location on the same chromosome. [[Linkage disequilibrium]] describes a situation in which some combinations of genes or genetic markers occur more or less frequently in a population than would be expected from their distances apart. This concept is applied when searching for a gene that may cause a particular [[disease]]. This is done by comparing the occurrence of a specific [[DNA sequence]] with the appearance of a disease. When a high correlation between the two is found, it is likely that the appropriate gene sequence is really closer<ref name = "Darling" />

==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}}

== See also ==
* [[Unequal crossing over]]
* [[Coefficient of coincidence]]
* [[Genetic distance]]
* [[Independent assortment]]
* [[Mitotic crossover]]
* [[Recombinant frequency]]

== References ==
{{Reflist}}

{{Genetic recombination}}
{{Authority control}}

[[Category:Cellular processes]]
[[Category:Modification of genetic information]]
[[Category:Molecular genetics]]