The 2R hypothesis or Ohno's hypothesis, first proposed by
Susumu Ohno in 1970,[1] is a
hypothesis that the genomes of the early
vertebrate lineage underwent two whole
genome duplications, and thus modern vertebrate genomes reflect
paleopolyploidy. The name derives from the 2 rounds 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.[2]
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,[2] the version of the genome duplication hypothesis from which 2R hypothesis takes its name appears in Holland et al.[3] and the term was coined by Austin L. Hughes.[4]
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.[5]
Later evidence
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.[6] However, this analysis did not examine vertebrates, so could say nothing about later duplication events.[7] (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.[8]) 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.[9] Paralogy regions were generally in sets of four. Second, cloning of
Hox genes in lancelet revealed presence of a single
Hox gene cluster,[10] 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.[7] 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.
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.[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, because
recombination could have occurred between the closely related chromosomes generated by
polyploidy,[14][15] because inappropriate genes had been compared[16] and because different predictions are made if genome duplication occurred through
hybridisation between species.[17] 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.[18][19] 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,[20] and that these duplications occurred after vertebrates had diverged from
tunicates[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 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."[23]
Ohnology
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.[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 containing
Hox 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 class
homeobox genes and many more
gene families,[28][29][30] and parts of human chromosomes 13, 4, 5 and X containing the
ParaHox genes and their neighbors.[31] The
Major histocompatibility complex (MHC) on human chromosome 6 has paralogy regions on chromosomes 1, 9 and 19.[32] Much of the
human genome seems to be assignable to paralogy regions.[33]
References
^Ohno, Susumu (1970). Evolution by Gene Duplication. London: Allen and Unwin,
ISBN0-04-575015-7.
^Schmidtke, Jörg; Weiler, Conrad; Kunz, Brigitte; Engel, Wolfgang (1977). "Isozymes of a tunicate and a cephalochordate as a test of polyploidisation in chordate evolution". Nature. 266 (5602): 532–533.
Bibcode:
1977Natur.266..532S.
doi:
10.1038/266532a0.
PMID859619.
S2CID4255382.
^Lundin, LG (April 1993). "Evolution of the vertebrate genome as reflected in paralogous chromosomal regions in man and the house mouse". Genomics. 16 (1): 1–19.
doi:
10.1006/geno.1993.1133.
PMID8486346.
^Hughes, AL (May 1999). "Phylogenies of developmentally important proteins do not support the hypothesis of two rounds of genome duplication early in vertebrate history". Journal of Molecular Evolution. 48 (5): 565–76.
Bibcode:
1999JMolE..48..565H.
doi:
10.1007/PL00006499.
PMID10198122.
S2CID24897399.
^Ruddle FH, Bentley KL, Murtha MT, Risch N (1994). "Gene loss and gain in the evolution of the vertebrates". Development. 1994: 155–61.
doi:
10.1242/dev.1994.Supplement.155.
PMID7579516.