Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The evolution of gene duplications: classifying and distinguishing between models

Nature Reviews Genetics volume 11, pages 97–108 (2010)Cite this article

Subjects

Key Points

  • Models of gene duplication can be classified into four major categories according to the mode of selection in the early phases of the evolution of the duplicated copies.

  • The evolutionary and population genetic assumptions for each model are described in this Review.

  • Many models show that under certain conditions, a newly arisen duplicated copy of a coding gene can be stably maintained by selection after it is fixed in the population.

  • Summaries of several models for the evolution and maintenance of gene duplications are provided. They have different evolutionary predictions in the phases before the final fate of the duplicated copy is determined.

  • The necessary data and the experimental designs to obtain such data that are needed to distinguish between the different models are described. The synonymous–non-synonymous ratio of divergence between duplicated copies is not informative for distinguishing between different models.

  • A pertinent issue in the evolution of gene duplications is the role of selection in their fixation. To resolve this issue, it is necessary to obtain polymorphisms in and around copy-number variants.

  • Gene conversion between duplicates plays an important part in the early stages of the evolution of duplicated genes, depending on the model in question, and can promote or inhibit the maintenance of the gene copy.

Abstract

Gene duplications and their subsequent divergence play an important part in the evolution of novel gene functions. Several models for the emergence, maintenance and evolution of gene copies have been proposed. However, a clear consensus on how gene duplications are fixed and maintained in genomes is lacking. Here, we present a comprehensive classification of the models that are relevant to all stages of the evolution of gene duplications. Each model predicts a unique combination of evolutionary dynamics and functional properties. Setting out these predictions is an important step towards identifying the main mechanisms that are involved in the evolution of gene duplications.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phases leading to the stable preservation of a duplicated gene.
Figure 2: Illustration of the models in categories I, II and III for gene-duplication evolution.

Similar content being viewed by others

References

  1. Kondrashov, F. A., Rogozin, I. B., Wolf, Y. I. & Koonin E. V. Selection in the evolution of gene duplications. Genome Biol. 3, research0008.1–0008.9 (2002). A combination of a literature review and genome analysis that suggests that most recently duplicated genes are fixed by positive selection for increased dosages of genes that control responses to stress and other environmental factors.

  2. Conant, G. C. & Wolfe, K. H. Turning a hobby into a job: how duplicated genes find new functions. Nature Rev. Genet. 12, 938–950 (2008).

    Google Scholar 

  3. Van de Peer, Y. Computational approaches to unveiling ancient genome duplications. Nature Rev. Genet. 10, 752–763 (2004).

    Google Scholar 

  4. Ponting, C. P. The functional repertoires of metazoan genomes. Nature Rev. Genet. 9, 689–698 (2008).

    CAS  PubMed  Google Scholar 

  5. Wagner, G. P., Pavlicev, M. & Cheverud, J. M. The road to modularity. Nature Rev. Genet. 12, 921–931 (2007).

    Google Scholar 

  6. Singleton, A. B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841–841 (2003).

    CAS  PubMed  Google Scholar 

  7. Perry, G. H. et al. 2007. Diet and the evolution of human amylase gene copy number variation. Nature Genet. 39, 1256–1260 (2007).

    CAS  PubMed  Google Scholar 

  8. Bailey, J. A. & Eichler, E. E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Rev. Genet. 7, 552–564 (2006).

    CAS  PubMed  Google Scholar 

  9. Lynch, M. The Origins of Genome Architecture (Sinauer Associates, Sunderland, USA, 2007).

    Google Scholar 

  10. Innan, H. Population genetic models of duplicated genes. Genetica 137, 19–37 (2009).

    CAS  PubMed  Google Scholar 

  11. Hahn, M. W. Distinguishing among evolutionary models for the maintenance of gene duplicates. J. Hered. 100, 605–617 (2009).

    CAS  PubMed  Google Scholar 

  12. Wolfe, K. H. & Shields, D. C. Molecular evidence for an ancient duplication of the entire yeast genome. Nature 387, 708–713 (1997).

    CAS  PubMed  Google Scholar 

  13. Semple, C. & Wolf, K. H. Gene duplication and gene conversion in the Caenorhabditis elegans genome. J. Mol. Evol. 48, 555–564 (1999).

    CAS  PubMed  Google Scholar 

  14. Rozen, S. et al. Abundant gene conversion between arms of palindromes in human and ape chromosomes. Nature 423, 873–876 (2003).

    CAS  PubMed  Google Scholar 

  15. Gao, L. Z. & Innan, H. Very low gene duplication rate in the yeast genome. Science 306, 1367–1370 (2004).

    CAS  PubMed  Google Scholar 

  16. Ezawa, K., OOta, S. & Saitou, N. Genome-wide search of gene conversions in duplicated genes of mouse and rat. Mol. Biol. Evol. 23, 927–940 (2006).

    CAS  PubMed  Google Scholar 

  17. Osada, N. & Innan, H., Duplication and gene conversion in the Drosophila melanogaster genome. PLoS Genet. 4, e1000305 (2008).

    PubMed  PubMed Central  Google Scholar 

  18. Patterson, A. H. et al. The Sorghum bicolor genome and the diversification of grasses. Nature 457, 551–556 (2009).

    Google Scholar 

  19. Ohno, S. Evolution by Gene Duplication (Springer, New York, 1970). A classic and influential book that outlines one of the most widely cited models of gene duplication. It includes several of the author's intuitive ideas based on his cytological studies.

  20. Nei, M. Gene duplication and nucleotide substitution in evolution. Nature 221, 40–42 (1969).

    CAS  PubMed  Google Scholar 

  21. Kimura, M. & King, J. L. Fixation of a deleterious allele at one of two 'duplicate' loci by mutation pressure and random drift. Proc. Natl Acad. Sci. USA 76, 2858–2861 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Li, W. H. Rate of gene silencing at duplicate loci: a theoretical study and interpretation of data from tetraploid fishes. Genetics 95, 237–258 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Stoltzfus, A. On the possibility of constructive neutral evolution. J. Mol. Evol. 49, 169–181 (1999).

    CAS  PubMed  Google Scholar 

  24. Walsh, J. B. How often do duplicated genes evolve new functions? Genetics 139, 421–428 (1995). A detailed theoretical analysis of the conditions necessary for the evolution of a new function under the assumptions of the neofunctionalization model.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Watterson, G. A. On the time for gene silencing at duplicate loci. Genetics 105, 745–766 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Walsh, B. Population-genetic models of the fates of duplicate genes. Genetica 118, 279–294 (2003).

    CAS  PubMed  Google Scholar 

  27. Force, A. et al. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545 (1999). A detailed model of preservation of gene duplications through the accumulation of mutations that are damaging to gene function. It proposes that the accumulation and maintenance of gene copies can be an entirely neutral process.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lynch, M. & Force, A. The probability of duplicate gene preservation by subfunctionalization. Genetics 154, 459–473 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lynch, M., O'Hely, M., Walsh, B. & Force, A. The probability of preservation of a newly arisen gene duplicate. Genetics 159, 1789–1804 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rastogi, S. & Liberles, D. A. Subfunctionalization of duplicated genes as a transition state to neofunctionalization. BMC Evol. Biol. 5, 28 (2005).

    PubMed  PubMed Central  Google Scholar 

  31. Dermitzakis, E. T. & Clark, A. G. Differential selection after duplication in mammalian developmental genes. Mol. Biol. Evol. 18, 557–562 (2001).

    CAS  PubMed  Google Scholar 

  32. Li, W. H., Yang, J. & Gu, X. Expression divergence between duplicate genes. Trends Genet. 21, 602–607 (2005).

    PubMed  Google Scholar 

  33. Ganko, E. W., Meyers, B. C. & Vision, T. J. Divergence in expression between duplicated genes in Arabidopsis. Mol. Biol. Evol. 24, 2298–2309 (2007).

    CAS  PubMed  Google Scholar 

  34. Byun-McKay, S. A. & Geeta, R. Protein subcellular relocalization: a new perspective on the origin of novel genes. Trends Ecol. Evol. 22, 338–344 (2007).

    PubMed  Google Scholar 

  35. Marques, A. C., Vinckenbosch, N., Brawand, D. & Kaessmann, H. Functional diversification of duplicate genes through subcellular adaptation of encoded proteins. Genome Biol. 9, R54 (2008).

    PubMed  PubMed Central  Google Scholar 

  36. Hughes, A. L. The evolution of functionally novel proteins after gene duplication. Proc. Biol. Sci. Lond. B 256, 119–124 (1994). The first paper to propose positive selection as an important force in the long-term evolution of gene duplications.

    CAS  Google Scholar 

  37. Piatigorsky, J. et al. Gene sharing by D-crystallin and argininosuccinate lyase. Proc. Natl. Acad. Sci. USA 85, 3479–3483 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Oakley, T. H., Ostman, B. & Wilson, A. C. Repression and loss of gene expression outpaces activation and gain in recently duplicated fly genes. Proc. Natl Acad. Sci. USA 103, 11637–11641 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. James, L. C. & Tawfik, D. S. Conformational diversity and protein evolution — a 60-year-old hypothesis revisited. Trends Biochem. Sci. 28, 361–368 (2003).

    CAS  PubMed  Google Scholar 

  40. Des Marais, D. L. & Rausher, M. D. Escape from adaptive conflict after duplication in an anthocyanin pathway gene. Nature 454, 762–765 (2008).

    CAS  PubMed  Google Scholar 

  41. Anderson, R. P. & Roth, J. R. Tandem genetic duplications in phage and bacteria. Annu. Rev. Microbiol. 31, 473–505 (1977).

    CAS  PubMed  Google Scholar 

  42. Koch, A. L. Evolution of antibiotic resistance gene function. Microbiol. Rev. 45, 355–378 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Velkov, V. V. Gene amplification in prokaryotic and eukaryotic systems. Genetica 18, 529–543 (1982).

    CAS  Google Scholar 

  44. Stark, G. R. & Wahl, G. M. Gene amplification. Annu. Rev. Biochem. 53, 447–491 (1984).

    CAS  PubMed  Google Scholar 

  45. Romero, D. & Palacios, R. Gene amplification and genomic plasticity in prokaryotes. Annu. Rev. Genet. 31, 91–111 (1997).

    CAS  PubMed  Google Scholar 

  46. Brown, C. J., Todd, K. M. & Rosenzweig, R. F. Multiple duplications of yeast hexose transport genes in response to selection in a glucose-limited environment. Mol. Biol. Evol. 15, 931–942 (1998).

    CAS  PubMed  Google Scholar 

  47. Guillemaud, T. et al. Quantitative variation and selection of esterase gene amplification in Culex pipiens. Heredity 83, 87–99 (1999).

    CAS  PubMed  Google Scholar 

  48. Kondrashov, F. A. & Kondrashov, A. S. Role of selection in fixation of gene duplications. J. Theor. Biol. 239, 141–151 (2006).

    CAS  PubMed  Google Scholar 

  49. Kondrashov, F. A. & Koonin, E. V. A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplication. Trends Genet. 20, 287–291 (2004). This paper applies the metabolic dosage theory that is commonly applied to genetic dominance to study the relationship between gene dosage and gene duplications.

    CAS  PubMed  Google Scholar 

  50. Veitia, R. A. Gene dosage balance: deletions, duplications and dominance. Trends Genet. 21, 33–35 (2005).

    CAS  PubMed  Google Scholar 

  51. Sugino, R. P. & Innan, H. Selection for more of the same product as a force to enhance concerted evolution of duplicated genes. Trends Genet. 22, 642–644 (2006).

    CAS  PubMed  Google Scholar 

  52. Francino, M. P. An adaptive radiation model for the origin of new gene functions. Nature Genet. 37, 573–577 (2005).

    CAS  PubMed  Google Scholar 

  53. Haldane, J. B. S. The part played by recurrent mutation in evolution. Am. Nat. 67, 5–19 (1933).

    Google Scholar 

  54. Fisher, R. A. The sheltering of lethals. Am. Nat. 69, 446–455 (1935).

    Google Scholar 

  55. Wright, S. Physiological and evolutionary theories of dominance. Am. Nat. 68, 24–53 (1934).

    Google Scholar 

  56. Fisher, R. A. The possible modification of the response of the wild type to recurrent mutations. Am. Nat. 62, 115–126 (1928).

    Google Scholar 

  57. Clark, A. G. Invasion and maintenance of a gene duplication. Proc. Natl Acad. Sci. USA. 91, 2950–2954 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lynch, M. & Katju, V. The altered evolutionary trajectories of gene duplicates. Trends Genet. 20, 544–549 (2004).

    CAS  PubMed  Google Scholar 

  59. Katju, V. & Lynch, M. On the formation of novel genes by duplication in the Caenorhabditis elegans genome. Mol. Biol. Evol. 23, 1056–1067 (2006).

    CAS  PubMed  Google Scholar 

  60. Lercher, M. J., Blumenthal, T. & Hurst, L. D. Coexpression of neighboring genes in Caenorhabditis elegans is mostly due to operons and duplicate genes. Genome Res. 13, 238–243 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Long, M. & Langley, C. H. Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila. Science 260, 91–95 (1993).

    CAS  PubMed  Google Scholar 

  62. Long, M., Betran, E., Thornton, K. & Wang, W. The origin of new genes: glimpses from the young and old. Nature Rev. Genet. 4, 865–875 (2003).

    CAS  PubMed  Google Scholar 

  63. Vinckenbosch, N., Dupanloup, I. & Kaessmann, H. Evolutionary fate of retroposed gene copies in the human genome. Proc. Natl Acad. Sci. USA 103, 3220–3225 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Aharoni, A. et al. The 'evolvability' of promiscuous protein functions. Nature Genet. 37, 73–76 (2005).

    CAS  PubMed  Google Scholar 

  65. Spofford, J. B. Heterosis and the evolution of duplications. Am. Nat. 103, 407–432 (1969). This paper suggested that a duplication of a locus for which there is a heterozygote advantage can be immediately beneficial.

    Google Scholar 

  66. Proulx, S. R. & Phillips, P. C. Allelic divergence precedes and promotes gene duplication. Evolution 60, 881–892 (2006).

    CAS  PubMed  Google Scholar 

  67. Muller, H. J. Genetic variability, twin hybrids and constant hybrids, in a case of balanced lethal factors. Genetics 3, 422–499 (1918).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Otto, S. P. & Yong, P. The evolution of gene duplicates. Adv. Genet. 46, 451–483 (2002).

    CAS  PubMed  Google Scholar 

  69. Penn, D. J., Damjanovich, K. & Potts, W. K. MHC heterozygosity confers a selective advantage against multiple-strain infections Proc. Natl Acad. Sci. USA 99, 11260–11264 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Doherty, P. C. & Zinkernagel, R. M. A biological role for the major histocompatibility antigens. Lancet 1, 1406–1409 (1975).

    CAS  PubMed  Google Scholar 

  71. Papp, B., Pál, C. & Hurst, L. D. Dosage sensitivity and the evolution of gene families in yeast. Nature 424, 194–197 (2003).

    CAS  PubMed  Google Scholar 

  72. Birchler, J. A. & Veitia, R. A. The gene balance hypothesis: from classical genetics to modern genomics. Plant Cell. 19, 395–402 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Liang, H., Plazonic, K. R., Chen, J., Li, W.-H. & Fernández, A. Protein under-wrapping causes dosage sensitivity and decreases gene duplicability. PLoS Genet. 4, e11 (2008).

    PubMed  PubMed Central  Google Scholar 

  74. Moore, R. C. & Purugganan, M. D. The early stages of duplicate gene evolution. Proc. Natl Acad. Sci. USA 100, 15682–15687 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    CAS  PubMed  Google Scholar 

  76. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Emerson, J. J., Cardoso-Moreira, M., Borevitz, J. O. & Long, M. Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster. Science 320, 1629–1631 (2008).

    CAS  PubMed  Google Scholar 

  78. Stranger, B. E. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kreitman, M. Methods to detect selection in populations with applications to the human. Annu. Rev. Genome Hum. Genet. 1, 539–559 (2000).

    CAS  Google Scholar 

  80. Neilsen, R. Molecular signatures of natural selection. Annu. Rev. Genet. 39, 197–218 (2005).

    Google Scholar 

  81. Hurst, L. D. Genetics and the understanding of selection. Nature Rev. Genet. 10, 83–93 (2009).

    CAS  PubMed  Google Scholar 

  82. Petes, T. D. & Hill, C. W. Recombination between repeated genes in microorganisms. Annu. Rev. Genet. 22, 147–168 (1988).

    CAS  PubMed  Google Scholar 

  83. Chen, J. M., Cooper, D. N., Chuzhanova, N., Ferec, C. & Patrinos, G. P. Gene conversion: mechanisms, evolution and human disease. Nature Rev. Genet. 8, 762–775 (2007).

    CAS  PubMed  Google Scholar 

  84. Teshima, K. M. & Innan, H. The effect of gene conversion on the divergence between duplicated genes. Genetics 166, 1553–1560 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Mano, S. & Innan, H. The evolutionary rate of duplicated genes under concerted evolution. Genetics 180, 493–505 (2008).

    PubMed  PubMed Central  Google Scholar 

  86. Ohta, T. Role of diversifying selection and gene conversion in evolution of major histocompatibility complex loci. Proc. Natl Acad. Sci. USA 88, 6716–6720 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Takuno, S., Nishio, T., Satta. Y. & Innan, H. Preservation of a pseudogene by gene conversion and diversifying selection. Genetics 180, 517–531 (2008).

    PubMed  PubMed Central  Google Scholar 

  88. Innan, H. A two-locus gene conversion model with selection and its application to the human RHCE and RHD genes. Proc. Natl Acad. Sci. USA 100, 8793–8798 (2003). This paper considers the influence of gene conversion on the adaptive divergence of two recently duplicated genes, and establishes the conditions under which selection can overcome the homogenizing pressure of conversion.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bischof, J. M. et al. Genome-wide identification of pseudogenes capable of disease-causing gene conversion. Hum. Mutat. 27, 545–552 (2006).

    CAS  PubMed  Google Scholar 

  90. Ohta, T. Allelic and nonallelic homology of a supergene family. Proc. Natl Acad. Sci. USA 79, 3251–3254 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Innan, H. The coalescent and infinite-site model of a small multigene family. Genetics 163, 803–810 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Teshima, K. M. & Innan, H. Neofunctionalization of duplicated genes under the pressure of gene conversion. Genetics 178, 1385–1398 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Lynch for insightful comments on the manuscript.

Author information

Authors and Affiliations

  1. Graduate University for Advanced Studies, Kanagawa, 240-0193, Hayama, Japan

    Hideki Innan

  2. PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan

    Hideki Innan

  3. Bioinformatics and Genomics Programme, Centre for Genomic Regulation, C/Dr Aiguader 88, Barcelona Biomedical Research Park Building, Barcelona, 08003, Spain

    Fyodor Kondrashov

Authors
  1. Hideki Innan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fyodor Kondrashov
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Hideki Innan's homepage

Fyodor Kondrashov's homepage

Glossary

Gene duplication

The emergence of a heritable copy of a gene.

Neofunctionalization

The random acquisition of a new function in the course of the accumulation of neutral mutations in duplicated genes.

Subfunctionalization

The process of the accumulation of degenerate mutations in gene copies that subdivides gene function among the duplicated genes. This term has been introduced to describe the mechanism of the duplication–degeneration–complementation model, but it is often used indiscriminately to describe any subdivision of function.

Specialization

A process of improvement of different aspects of gene function in each gene copy, which is driven by positive selection.

Non-functionalization

The process of the accumulation of neutral mutations in a duplicated gene that renders the gene copy non-functional. Also known as pseudogenization.

Degenerate mutation

A mutation that does not affect fitness but is damaging to gene function.

Promiscuous function

A secondary, possibly neutral function that is performed by a protein with another primary function. It is an example of gene sharing.

Gene sharing

An early term describing situations in which a gene has more than one function. Modern studies describe such genes as multifunctional.

Gene dosage

The amount of product produced from a gene; broadly equivalent to gene expression.

Gene amplification

The emergence of a non-heritable extra copy of a gene in a somatic tissue. In microorganisms this term can be used interchangeably with gene duplication.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Innan, H., Kondrashov, F. The evolution of gene duplications: classifying and distinguishing between models. Nat Rev Genet 11, 97–108 (2010). https://doi.org/10.1038/nrg2689

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2689

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing