2R hypothesis

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.{{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}}

In 1977, Schmidtke and colleagues showed that isozyme complexity is similar in lancelets and tunicates, contradicting a prediction of Ohno's hypothesis that genome duplication occurred in the common ancestor of lancelets and vertebrates.{{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}} However, this analysis did not examine vertebrates, so could say nothing about later duplication events.{{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}} (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.{{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}}) 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.{{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}} Paralogy regions were generally in sets of four. Second, cloning of Hox genes in lancelet revealed presence of a single Hox gene cluster,{{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}} 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. 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|year= 2005|volume=3|issue=10|pages=e314|doi=10.1371/journal.pbio.0030314|pmid= 16128622 |pmc=1197285 |doi-access=free }} {{open access}}]]

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 duplications 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.{{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}}{{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}} 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 recombination could have occurred between the closely related chromosomes generated by polyploidy,{{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}}{{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}} because inappropriate genes had been compared{{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}} and because different predictions are made if genome duplication occurred through hybridisation between species.{{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}} 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.{{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}}{{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}} 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,{{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}} and that these duplications occurred after vertebrates had diverged from tunicates and lancelets.{{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|year= 2008|volume=453|issue=7198|pages=1064–71|pmid=18563158|doi=10.1038/nature06967|doi-access=free |bibcode=2008Natur.453.1064P }} 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".

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".{{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}} Michael Benton, in the 2014 edition of 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."{{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}}

Ohnologous genes are paralogous genes that have originated by a process of this 2R duplication. The name was first given in honour of Susumu Ohno by Ken Wolfe.{{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 }} 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).{{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 }}{{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 }}

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,{{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 }} genes in human chromosomes 4, 5, 8 and 10 containing neuropeptide receptor genes, NK class homeobox genes and many more gene families,{{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 }}{{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 }}{{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 }} and parts of human chromosomes 13, 4, 5 and X containing the ParaHox genes and their neighbors.{{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 }} The Major histocompatibility complex (MHC) on human chromosome 6 has paralogy regions on chromosomes 1, 9 and 19.{{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}} Much of the human genome seems to be assignable to paralogy regions.{{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 }}

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Category:Biological hypotheses

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Category:Molecular evolution

Category:Molecular genetics