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{{Short description|Paleopolyploidy in early vertebrates}}
The '''2R hypothesis''' or '''Ohno's hypothesis''', first proposed by [[Susumu Ohno]] in 1970,<ref name=Ohno70>Ohno, Susumu (1970). ''Evolution by Gene Duplication.'' London: Allen and Unwin, {{ISBN|0-04-575015-7}}.</ref> is a [[hypothesis]] that the genomes of the early [[vertebrate]] lineage underwent two whole [[genome duplication]]s, and thus modern vertebrate genomes reflect [[paleopolyploidy]].  The name derives from the '''''2 r'''ounds'' of duplication originally hypothesized by Ohno, but refined in a 1994 version, and the term ''2R hypothesis'' was probably coined in 1999. Variations in the number and timings of genome duplications typically still are referred to as examples of the 2R hypothesis.<ref name=Hokamp>{{cite journal | last1 = Hokamp | first1 = K | last2 = McLysaght | first2 = A | last3 = Wolfe | first3 = KH|authorlink3=Kenneth H. Wolfe|authorlink2=Aoife McLysaght | title = The 2R hypothesis and the human genome sequence | journal = Journal of Structural and Functional Genomics | volume = 3 | issue = 1–4 | pages = 95–110 | year = 2003 | pmid = 12836689 | doi = 10.1023/A:1022661917301 | s2cid = 18856088 }}</ref>

The 2R hypothesis has been the subject of much research and controversy; however, with growing support from genome data, including the [[human genome]], the balance of opinion has shifted strongly in favour of support for the hypothesis. According to Karsten Hokamp, [[Aoife McLysaght]] and [[Kenneth H. Wolfe]],<ref name=Hokamp/> the version of the genome duplication hypothesis from which 2R hypothesis takes its name appears in Holland ''et al.''<ref name=Holland>{{cite journal | last1 = Holland | first1 = PW | last2 = Garcia-Fernàndez | first2 = J | last3 = Williams | first3 = NA | last4 = Sidow | first4 = A | title = Gene duplications and the origins of vertebrate development | journal = Development. Supplement | pages = 125–33 | year = 1994 | pmid = 7579513 }}</ref> and the term was coined by Austin L. Hughes.<ref name=Hughes>{{cite journal | last1 = Hughes | first1 = Austin L. | title = Phylogenies of developmentally important proteins do not support the hypothesis of two rounds of genome duplication early in vertebrate history | journal = [[Journal of Molecular Evolution]] | volume = 48 | issue = 5 | pages = 565–76 | year = 1999 | pmid = 10198122 | doi = 10.1007/PL00006499 | bibcode = 1999JMolE..48..565H | s2cid = 24897399 }}</ref>

==Ohno's argument==
Ohno presented the first version of the 2R hypothesis as part of his larger argument for the general importance of [[gene duplication]] in [[evolution]].  Based on relative genome sizes and [[isozyme]] analysis, he suggested that ancestral fish or amphibians had undergone at least one and possibly more cases of "tetraploid evolution". He later added to this argument the evidence that most [[paralogous genes]] in vertebrates do not demonstrate [[genetic linkage]].  Ohno argued that linkage should be expected in the case of individual [[tandem duplications]] (in which a duplicate gene is added adjacent to the original gene on the same chromosome), but not in the case of chromosome duplications.<ref name=Makalowski>{{cite journal | last1 = Makalowski | first1 = Wojciech | title = Are we polyploids? A brief history of one hypothesis | journal = [[Genome Research]] | volume = 11 | issue = 5 | pages = 667–70 | year = 2001 | pmid = 11337465 | doi = 10.1101/gr.188801 | doi-access = free }} {{free access}}</ref>

==Later evidence==
In 1977, Schmidtke and colleagues showed that [[isozyme]] complexity is similar in [[lancelet]]s and [[tunicates]], contradicting a prediction of Ohno's hypothesis that [[genome duplication]] occurred in the common ancestor of lancelets and [[vertebrates]].<ref>{{cite journal|last1=Schmidtke|first1=Jörg|last2=Weiler |first2=Conrad |last3=Kunz |first3=Brigitte |last4=Engel |first4=Wolfgang|title=Isozymes of a tunicate and a cephalochordate as a test of polyploidisation in chordate evolution|journal=Nature|year=1977|volume=266|issue=5602|pages=532–533|doi=10.1038/266532a0|pmid=859619|bibcode=1977Natur.266..532S|s2cid=4255382}}</ref> However, this analysis did not examine vertebrates, so could say nothing about later duplication events.<ref name="Holland 2003 75–84">{{cite journal|last=Holland|first=PW|title=More genes in vertebrates?|journal=Journal of Structural and Functional Genomics|year=2003|volume=3|issue=1–4|pages=75–84|pmid=12836687|doi=10.1023/a:1022656931587|s2cid=35418674}} {{closed access}}</ref> (Furthermore, much later [[molecular phylogenetics]] has shown that vertebrates are more closely related to tunicates than to lancelets, thus negating the logic of this analysis.<ref>{{cite journal|last=Delsuc|first=F|author2=Brinkmann, H |author3=Chourrout, D |author4=Philippe, H|title=Tunicates and not cephalochordates are the closest living relatives of vertebrates.|journal=Nature|year=2006|volume=439|issue=7079|pages=965–8|pmid=16495997|doi=10.1038/nature04336|bibcode=2006Natur.439..965D|s2cid=4382758|url=https://hal.archives-ouvertes.fr/halsde-00315436/file/Delsuc-Nature06_HAL.pdf}} {{closed access}}</ref>) The 2R hypothesis saw a resurgence of interest in the 1990s for two reasons. First, gene mapping data in humans and mice revealed extensive [[paralogy regions]] - sets of genes on one chromosome related to sets of genes on another chromosome in the same species, indicative of duplication events in evolution.<ref>{{cite journal|last=Lundin|first=LG|title=Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse.|journal=Genomics|date=April 1993|volume=16|issue=1|pages=1–19|pmid=8486346|doi=10.1006/geno.1993.1133}}</ref> Paralogy regions were generally in sets of four. Second, cloning of [[Hox gene]]s in lancelet revealed presence of a single [[Hox gene cluster]],<ref>{{cite journal|last=Garcia-Fernández|first=J|author2=Holland, PW|title=Archetypal organization of the amphioxus Hox gene cluster.|journal=Nature|date=Aug 18, 1994|volume=370|issue=6490|pages=563–6|pmid=7914353|doi=10.1038/370563a0|bibcode=1994Natur.370..563G|s2cid=4329696}}</ref> in contrast to the four clusters in humans and mice. Data from additional [[gene families]] revealed a common one-to-many rule when lancelet and vertebrate genes were compared.<ref name="Holland 2003 75–84"/> Taken together, these two lines of evidence suggest that two genome duplications occurred in the ancestry of vertebrates, after it had diverged from the [[cephalochordate]] evolutionary lineage.

[[File:Patró de gens - Hipòtesi 2R.png|thumb|300px|right|Pattern predicted for the relative locations of paralogous genes from two genome duplications<ref name="Dehal e314">{{cite journal|last=Dehal|first=Paramvir|author2=Boore, Jeffrey L.|title=Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate|journal=[[PLOS Biology]]|year= 2005|volume=3|issue=10|pages=e314|doi=10.1371/journal.pbio.0030314|pmid= 16128622 |pmc=1197285 |doi-access=free }} {{open access}}</ref>]]
Controversy about the 2R hypothesis hinged on the nature of [[paralogy regions]]. It is not disputed that human [[chromosomes]] bear sets of genes related to sets of genes on other chromosomes; the controversy centres on whether they were generated by large-scale duplications that doubled all the genes at the same time, or whether a series of individual [[gene duplication]]s occurred followed by [[chromosomal rearrangement]] to shuffle sets of genes together. Hughes and colleagues found that [[phylogenetic trees]] built from different [[gene families]] within [[paralogy regions]] had different shapes, suggesting that the gene families had different evolutionary histories.<ref>{{cite journal|last=Hughes|first=AL|title=Phylogenies of developmentally important proteins do not support the hypothesis of two rounds of genome duplication early in vertebrate history|journal=Journal of Molecular Evolution|date=May 1999|volume=48|issue=5|pages=565–76|pmid=10198122|doi=10.1007/PL00006499|bibcode=1999JMolE..48..565H|s2cid=24897399}}</ref><ref>{{cite journal|last=Hughes|first=Austin L.|author2=Friedman, Robert|title=2R or not 2R: Testing hypotheses of genome duplication in early vertebrates|journal=Journal of Structural and Functional Genomics|year= 2003|volume=3|issue=1/4|pages=85–93|doi=10.1023/A:1022681600462|title-link=genome duplication|pmid=12836688|s2cid=835565}}</ref> This was suggested to be inconsistent with the 2R hypothesis. However, other researchers have argued that such 'topology tests' do not test 2R rigorously, because [[Genetic recombination|recombination]] could have occurred between the closely related chromosomes generated by [[polyploidy]],<ref>{{cite journal|last=Furlong|first=RF|author2=Holland, PW|title=Were vertebrates octoploid?|journal=Philosophical Transactions of the Royal Society B|year=2002|volume=357|issue=1420|pages=531–44|pmid=12028790|doi=10.1098/rstb.2001.1035|pmc=1692965}}</ref><ref>{{cite journal|last=Lynch|first=VJ|author2=Wagner, GP|title=Multiple chromosomal rearrangements structured the ancestral vertebrate Hox-bearing protochromosomes.|journal=[[PLOS Genetics]]|year=2009|volume=5|issue=1|pages=e1000349|pmid=19165336|doi=10.1371/journal.pgen.1000349|pmc=2622764 |doi-access=free }} {{open access}}</ref> because inappropriate genes had been compared<ref>{{cite journal|last=Larhammar|first=D.|author2=Josephson, M|title=The Human Hox-bearing Chromosome Regions Did Arise by Block or Chromosome (or Even Genome) Duplications|journal=[[Genome Research]]|year= 2002|volume=12|issue=1|pages=1910–1920|doi=10.1101/gr.445702|pmc=187569|pmid=12466295}}</ref> and because different predictions are made if genome duplication occurred through [[hybrid (biology)|hybrid]]isation between species.<ref>{{cite journal|last=Spring|first=Jürg|title=Vertebrate evolution by interspecific hybridisation – are we polyploid?|journal=FEBS Letters|year= 1997|volume=400|issue=1|pages=2–8|doi=10.1016/S0014-5793(96)01351-8|pmid=9000502|doi-access=free|bibcode=1997FEBSL.400....2S }} {{free access}}</ref> In addition, several researchers were able to date duplications of gene families within [[paralogy regions]] consistently to the early evolution of vertebrates, after divergence from amphioxus, consistent with the 2R hypothesis.<ref>{{cite journal|last=Abi-Rached|first=L|author2=Gilles, A |author3=Shiina, T |author4=Pontarotti, P |author5=Inoko, H |title=Evidence of en bloc duplication in vertebrate genomes.|journal=[[Nature Genetics]]|year=2002|volume=31|issue=1|pages=100–5|pmid=11967531|doi=10.1038/ng855|s2cid=8516649|doi-access=free}}</ref><ref>{{cite journal|last=Castro|first=LF|author2=Holland, PW|title=Chromosomal mapping of ANTP class homeobox genes in amphioxus: piecing together ancestral genomes.|journal=[[Evolution & Development]]|date=Sep–Oct 2003|volume=5|issue=5|pages=459–65|pmid=12950625|doi=10.1046/j.1525-142x.2003.03052.x|s2cid=38083087}}</ref> When complete [[genome sequences]] became available for vertebrates, ''[[Ciona intestinalis]]'' and lancelets, it was found that much of the [[human genome]] was arranged in [[paralogy regions]] that could be traced to large-scale duplications,<ref>{{cite journal|last=McLysaght|first=Aoife|authorlink1=Aoife McLysaght|author2=Hokamp, Karsten |author3=Wolfe, Kenneth H.|authorlink3=Kenneth H. Wolfe|title=Extensive genomic duplication during early chordate evolution|journal=Nature Genetics|year= 2002|volume=31|issue=2|pages=200–204|doi=10.1038/ng884|pmid=12032567|s2cid=8263376}}</ref> and that these duplications occurred after vertebrates had diverged from [[tunicates]]<ref name="Dehal e314"/>  and lancelets.<ref>{{cite journal|last=Putnam|first=NH|author2=Butts, T |author3=Ferrier, DE |author4=Furlong, RF |author5=Hellsten, U |author6=Kawashima, T |author7=Robinson-Rechavi, M |author8=Shoguchi, E |author9=Terry, A |author10=Yu, JK |author11=Benito-Gutiérrez, EL |author12=Dubchak, I |author13=Garcia-Fernàndez, J |author14=Gibson-Brown, JJ |author15=Grigoriev, IV |author16=Horton, AC |author17=de Jong, PJ |author18=Jurka, J |author19=Kapitonov, VV |author20=Kohara, Y |author21=Kuroki, Y |author22=Lindquist, E |author23=Lucas, S |author24=Osoegawa, K |author25=Pennacchio, LA |author26=Salamov, AA |author27=Satou, Y |author28=Sauka-Spengler, T |author29=Schmutz, J |author30=Shin-I, T |author31=Toyoda, A |author32=Bronner-Fraser, M |author33=Fujiyama, A |author34=Holland, LZ |author35=Holland, PW |author36=Satoh, N |author37=Rokhsar, DS|title=The amphioxus genome and the evolution of the chordate karyotype|journal=[[Nature (journal)|Nature]]|year= 2008|volume=453|issue=7198|pages=1064–71|pmid=18563158|doi=10.1038/nature06967|doi-access=free |bibcode=2008Natur.453.1064P }}</ref> This would date the two genome duplications to between 550 and 450 million years ago.

The controversy raging in the late 1990s was summarized in a 2001 review of the subject by Wojciech Makałowski, who stated that "the hypothesis of whole genome duplications in the early stages of vertebrate evolution has as many adherents as opponents".<ref name=Makalowski/>

In contrast, a more recent review in 2007 by Masanori Kasahara states that there is now "incontrovertible evidence supporting the 2R hypothesis" and that "a long-standing debate on the 2R hypothesis is approaching the end".<ref name=Kasahara>{{cite journal | last1 = Kasahara | first1 = Masanori | title = The 2R hypothesis: an update | journal = Current Opinion in Immunology | volume = 19 | issue = 5 | pages = 547–52 | year = 2007 | pmid = 17707623 | doi = 10.1016/j.coi.2007.07.009 }} {{closed access}}</ref> [[Michael Benton]], in the 2014 edition of ''[[Vertebrate Palaeontology (Benton)|Vertebrate Palaeontology]]'', states, "It turns out that, in places where [[amphioxus]] has a single gene, vertebrates often have two, three, or four equivalent genes as a result of two intervening whole-genome duplication events."<ref name="Benton2014">{{cite book|last=Benton|first=Michael|authorlink=Michael Benton|title=Vertebrate Palaeontology|url=https://books.google.com/books?id=qak-BAAAQBAJ&pg=PT92|access-date=19 December 2015|year=2014|publisher=Wiley|isbn=978-1-118-40764-6|page=92}}</ref>

==Ohnology==
Ohnologous genes are paralogous [[gene]]s that have originated by a process of this 2R [[Paleopolyploidy|duplication]]. The name was first given in honour of [[Susumu Ohno]] by [[Kenneth H. Wolfe|Ken Wolfe]].<ref>{{cite journal | vauthors = Wolfe K | title = Robustness--it's not where you think it is | journal = Nature Genetics | volume = 25 | issue = 1 | pages = 3–4 | date = May 2000 | pmid = 10802639 | doi = 10.1038/75560 | s2cid = 85257685 }}</ref> It is useful for evolutionary analysis because all ohnologues in a genome have been diverging for the same length of time (since their common origin in the whole genome duplication).<ref>{{cite journal | vauthors = McLysaght A, Makino T, Grayton HM, Tropeano M, Mitchell KJ, Vassos E, Collier DA | title = Ohnologs are overrepresented in pathogenic copy number mutations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 1 | pages = 361–6 | date = January 2014 | pmid = 24368850 | pmc = 3890797 | doi = 10.1073/pnas.1309324111 | bibcode = 2014PNAS..111..361M | doi-access = free }}</ref><ref>{{cite journal | vauthors = Makino T, McLysaght A | title = Ohnologs in the human genome are dosage balanced and frequently associated with disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 20 | pages = 9270–4 | date = May 2010 | pmid = 20439718 | pmc = 2889102 | doi = 10.1073/pnas.0914697107 | bibcode = 2010PNAS..107.9270M | doi-access = free }}</ref>

Well-studied ohnologous genes include genes in human chromosome 2, 7, 12 and 17 containing [[Hox gene]] clusters, [[collagen]] genes, [[keratin]] genes and other duplicated genes,<ref>{{cite journal | vauthors = Ruddle FH, Bentley KL, Murtha MT, Risch N | title = Gene loss and gain in the evolution of the vertebrates | journal = Development | pages = 155–61 | year = 1994 | volume = 1994 | doi = 10.1242/dev.1994.Supplement.155 | pmid = 7579516 }}</ref> genes in human chromosomes 4, 5, 8 and 10 containing neuropeptide receptor genes, NK class [[homeobox genes]] and many more [[gene families]],<ref>{{cite journal | vauthors = Pébusque MJ, Coulier F, Birnbaum D, Pontarotti P | title = Ancient large-scale genome duplications: phylogenetic and linkage analyses shed light on chordate genome evolution | journal = Molecular Biology and Evolution | volume = 15 | issue = 9 | pages = 1145–59 | date = September 1998 | pmid = 9729879 | doi = 10.1093/oxfordjournals.molbev.a026022 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Larsson TA, Olsson F, Sundstrom G, Lundin LG, Brenner S, Venkatesh B, Larhammar D | title = Early vertebrate chromosome duplications and the evolution of the neuropeptide Y receptor gene regions | journal = BMC Evolutionary Biology | volume = 8 | pages = 184 | date = June 2008 | issue = 1 | pmid = 18578868 | pmc = 2453138 | doi = 10.1186/1471-2148-8-184 | doi-access = free | bibcode = 2008BMCEE...8..184L }}</ref><ref>{{cite journal | vauthors = Pollard SL, Holland PW | title = Evidence for 14 homeobox gene clusters in human genome ancestry | journal = Current Biology | volume = 10 | issue = 17 | pages = 1059–62 | date = September 2000 | pmid = 10996074 | doi = 10.1016/S0960-9822(00)00676-X | s2cid = 32135432 | doi-access = free | bibcode = 2000CBio...10.1059P }}</ref> and parts of human chromosomes 13, 4, 5 and X containing the [[ParaHox]] genes and their neighbors.<ref>{{cite journal | vauthors = Mulley JF, Chiu CH, Holland PW | title = Breakup of a homeobox cluster after genome duplication in teleosts | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 27 | pages = 10369–10372 | date = July 2006 | pmid = 16801555 | pmc = 1502464 | doi = 10.1073/pnas.0600341103 | bibcode = 2006PNAS..10310369M | doi-access = free }}</ref> The [[Major histocompatibility complex]] (MHC) on human chromosome 6 has paralogy regions on chromosomes 1, 9 and 19.<ref>{{cite journal | vauthors = Flajnik MF, Kasahara M | title = Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system | journal = Immunity | volume = 15 | issue = 3 | pages = 351–62 | date = September 2001 | pmid = 11567626 | doi = 10.1016/S1074-7613(01)00198-4 |doi-access=free}}</ref> Much of the [[human genome]] seems to be assignable to paralogy regions.<ref>{{cite journal | vauthors = McLysaght A, Hokamp K, Wolfe KH | title = Extensive genomic duplication during early chordate evolution | journal = Nature Genetics | volume = 31 | issue = 2 | pages = 200–4 | date = June 2002 | pmid = 12032567 | doi = 10.1038/ng884 | s2cid = 8263376 }}</ref>

==References==
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[[Category:Biological hypotheses]]
[[Category:Genomics techniques]]
[[Category:Molecular evolution]]
[[Category:Molecular genetics]]