The 2R hypothesis or Ohno's hypothesis, first proposed by Susumu Ohno in 1970, is a contested hypothesis in genomics and molecular evolution suggesting that the genomes of the early vertebrate lineage underwent one or more complete genome duplications, and thus modern vertebrate genomes reflect paleopolyploidy. The name derives from the 2 rounds of duplication hypothesized by a 1994 version, and the term 2R hypothesis was probably coined in 1999; variations in the number of duplications typically still are referred to as examples of the 2R hypothesis. Since Ohno proposed the first version of it in Evolution by Gene Duplication, the 2R hypothesis has been the subject of much research, but even with recent data from the human genome, it remains a matter of scientific dispute.
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, 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.
The 2R hypothesis saw a resurgence of interest in the 1990s, with multiple suggestions for the time and number of duplications. Estimates for the dates of duplication events range from before 640 million years ago to after 450 million years ago. One argument for the hypothesis relies on the number of genes in mammals, which was previously estimated at around four times the number in invertebrate genomes (though more recent estimates are less than half that). Some analyses of gene families in human chromosomes have shown patterns that are not consistent with the 2R hypothesis. Parsimony analysis has produced some results that, while not supportive of the hypothesis, do not rule it out. According to a 2001 review of the subject by Wojciech Makałowski, "the hypothesis of whole genome duplications in the early stages of vertebrate evolution has as many adherents as opponents"; Makałowski argues that the overall balance of current evidence seems to be against it, but that it is not easily falsifiable because it can be modified to accommodate a wide range of data. Others analyzing duplications in the draft human genome sequence have claimed that genome data provides evidence of "extensive duplication" and that the parsimony tests that cast doubt on the hypothesis are of questionable validity. A 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". 
- Karsten Hokamp, Aoife McLysaght, and Kenneth H. Wolfe, "The 2R hypothesis and the human genome sequence", Journal of Structural and Functional Genomics, vol. 3, pp. 95-110 (2003). According to Hokamp, et al., the version of the genome duplication hypothesis from which 2R hypothesis takes its name is:
- Holland, P.W.H., Garcia-Fernandez, J., Williams, N.A. and Sidow, A. (1994) "Gene duplications and the origins of vertebrate development". Development, Suppl. 1994, 125–133.
- Hughes, A.L. (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, 565–576.
- Makałowski, Wojciech (2001-05-01). "Are We Polyploids? A Brief History of One Hypothesis". Genome Research. 11 (5): 667–670. doi:10.1101/gr.188801. Retrieved 2007-08-27.
- Karsten Hokamp, Aoife McLysaght, and Kenneth H. Wolfe, "The 2R hypothesis and the human genome sequence", Journal of Structural and Functional Genomics, vol. 3, pp. 95-110 (2003). p. 95
- Masanori Kasahara, "The 2R hypothesis: an update", "Current Opinion in Immunology " (2007), doi:10.1016/j.coi.2007.07.009
- Ohno, Susumu. Evolution by Gene Duplication. 1970.