The2R hypothesis orOhno's hypothesis, first proposed bySusumu Ohno in 1970,^[1] is ahypothesis that the genomes of the earlyvertebrate lineage underwent two wholegenome duplications, and thus modern vertebrate genomes reflectpaleopolyploidy. The name derives from the2 rounds of duplication originally hypothesized by Ohno, but refined in a 1994 version, and the term2R 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.^[2]

The 2R hypothesis has been the subject of much research and controversy; however, with growing support from genome data, including thehuman genome, the balance of opinion has shifted strongly in favour of support for the hypothesis. According to Karsten Hokamp,Aoife McLysaght andKenneth H. Wolfe,^[2] the version of the genome duplication hypothesis from which 2R hypothesis takes its name appears in Hollandet al.^[3] and the term was coined by Austin L. Hughes.^[4]

Ohno presented the first version of the 2R hypothesis as part of his larger argument for the general importance ofgene duplication inevolution. Based on relative genome sizes andisozyme 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 mostparalogous genes in vertebrates do not demonstrategenetic linkage. Ohno argued that linkage should be expected in the case of individualtandem 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.^[5]

In 1977, Schmidtke and colleagues showed thatisozyme complexity is similar inlancelets andtunicates, contradicting a prediction of Ohno's hypothesis thatgenome duplication occurred in the common ancestor of lancelets andvertebrates.^[6] However, this analysis did not examine vertebrates, so could say nothing about later duplication events.^[7] (Furthermore, much latermolecular phylogenetics has shown that vertebrates are more closely related to tunicates than to lancelets, thus negating the logic of this analysis.^[8]) The 2R hypothesis saw a resurgence of interest in the 1990s for two reasons. First, gene mapping data in humans and mice revealed extensiveparalogy 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.^[9] Paralogy regions were generally in sets of four. Second, cloning ofHox genes in lancelet revealed presence of a singleHox gene cluster,^[10] in contrast to the four clusters in humans and mice. Data from additionalgene families revealed a common one-to-many rule when lancelet and vertebrate genes were compared.^[7] Taken together, these two lines of evidence suggest that two genome duplications occurred in the ancestry of vertebrates, after it had diverged from thecephalochordate evolutionary lineage.

Controversy about the 2R hypothesis hinged on the nature ofparalogy regions. It is not disputed that humanchromosomes 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 individualgene duplications occurred followed bychromosomal rearrangement to shuffle sets of genes together. Hughes and colleagues found thatphylogenetic trees built from differentgene families withinparalogy regions had different shapes, suggesting that the gene families had different evolutionary histories.^[12][13] This was suggested to be inconsistent with the 2R hypothesis. However, other researchers have argued that such 'topology tests' do not test 2R rigorously, becauserecombination could have occurred between the closely related chromosomes generated bypolyploidy,^[14][15] because inappropriate genes had been compared^[16] and because different predictions are made if genome duplication occurred throughhybridisation between species.^[17] In addition, several researchers were able to date duplications of gene families withinparalogy regions consistently to the early evolution of vertebrates, after divergence from amphioxus, consistent with the 2R hypothesis.^[18][19] When completegenome sequences became available for vertebrates,Ciona intestinalis and lancelets, it was found that much of thehuman genome was arranged inparalogy regions that could be traced to large-scale duplications,^[20] and that these duplications occurred after vertebrates had diverged fromtunicates^[11] and lancelets.^[21] 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".^[5]

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".^[22]Michael Benton, in the 2014 edition ofVertebrate Palaeontology, states, "It turns out that, in places whereamphioxus has a single gene, vertebrates often have two, three, or four equivalent genes as a result of two intervening whole-genome duplication events."^[23]

Ohnologous genes are paralogousgenes that have originated by a process of this 2Rduplication. The name was first given in honour ofSusumu Ohno byKen Wolfe.^[24] 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).^[25][26]

Well-studied ohnologous genes include genes in human chromosome 2, 7, 12 and 17 containingHox gene clusters,collagen genes,keratin genes and other duplicated genes,^[27] genes in human chromosomes 4, 5, 8 and 10 containing neuropeptide receptor genes, NK classhomeobox genes and many moregene families,^[28][29][30] and parts of human chromosomes 13, 4, 5 and X containing theParaHox genes and their neighbors.^[31] TheMajor histocompatibility complex (MHC) on human chromosome 6 has paralogy regions on chromosomes 1, 9 and 19.^[32] Much of thehuman genome seems to be assignable to paralogy regions.^[33]

• Biological hypotheses
• Genomics techniques
• Molecular evolution
• Molecular genetics

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