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.

Adaptive evolution and explosive speciation: the cichlid fish model

Nature Reviews Genetics volume 5, pages 288–298 (2004)Cite this article

Key Points

  • The spectacular radiation of 2,000 species of cichlid fishes in East Africa is an ideal model system and natural laboratory for studying evolutionary processes.

  • The explosive speciation of cichlids is probably due to a combination of forces, including natural selection on ecological traits, sexual selection on male colour patterns, and possibly genetic conflicts over the sex ratio.

  • Genomic approaches promise to unify theoretical and empirical studies by identifying the genes that are responsible for adaptive differences.

  • An array of genomic resources has been developed for cichlids, including genetic and physical maps, and microarrays of expressed sequences.

  • Quantitative trait mapping is identifying the genetic basis for differences in jaw and tooth shape among species.

  • Orange-blotch, a sex-linked intraspecific colour polymorphism that features in several models of speciation, is due to a single dominant gene in a Lake Malawi cichlid.

  • Marked variation in visual spectral sensitivity among species is due to differences in the expression of the opsin genes.

  • The development of new model systems for the study of evolution and speciation is now practical, and will provide another window on the function of vertebrate genes.

Abstract

The cost of DNA sequencing continues to fall, which makes it feasible to develop genomic resources for new model species that are well suited for studying questions in evolutionary biology. The thousands of closely related cichlid fishes in the lakes of East Africa are an ideal model system for understanding the genetic basis of vertebrate speciation. Genomic techniques are helping to integrate empirical and theoretical studies by identifying the genes that underlie the phenotypic differences among species.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Three-stage radiation of cichlids in Lake Malawi.
Figure 2: Diversity of bower form in Lake Malawi cichlids.
Figure 3: Intraspecific colour polymorphisms.

References

  1. Darwin, C. On the Origins of Species by Means of Natural Selection or The Preservation of Favoured Races in the Struggle for Life (John Murray, London, 1859).

    Book  Google Scholar 

  2. Mayr, E. Animal Species and Evolution (Belknap Press, Cambridge, Massachusetts, 1963).

    Book  Google Scholar 

  3. Rice, W. R. in Endless Forms: Species and Speciation (eds Howard, D. J. & Berlocher, S. H.) 261–270 (Oxford University Press, New York, 1998).

    Google Scholar 

  4. Lynch, M. & Force, A. G. The origin of interspecific genomic incompatability via gene duplication. Am. Nat. 156, 590–605 (2000).

    Article  PubMed  Google Scholar 

  5. Schluter, D. Ecology and the origin of species. Trends Ecol. Evol. 16, 372–380 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Civetta, A. & Singh, R. S. Broad-sense sexual selection, sex gene pool evolution, and speciation. Genome 42, 1033–1041 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Schliewen, U. K., Tautz, D. & Paabo, S. Sympatric speciation suggested by monophyly of crater lake cichlids. Nature 368, 629–632 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. McKaye, K. R. et al. Behavioral, morphological and genetic evidence of divergence of the Midas cichlid species complex in two Nicaraguan crater lakes. Cuadernos de la Investigación de la UCA 12, 19–47 (2002).

    Google Scholar 

  9. Turner, G. F., Seehausen, O., Knight, M. E., Allender, C. J. & Robinson, R. L. How many species of cichlid fishes are there in African lakes? Mol. Ecol. 10, 793–806 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Genner, M. J. et al. How does the taxonomic status of allopatric populations influence species richness with African cichlid fish assemblages? J. Biogeogr. 31, 93–102 (2004).

    Article  Google Scholar 

  11. Danley, P. D., & Kocher, T. D. Speciation in rapidly diverging systems: lessons from Lake Malawi. Mol. Ecol. 10, 1075–1086 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Streelman, J. T. & Danley, P. D. The stages of vertebrate evolutionary radiation. Trends Ecol. Evol. 18, 126–131 (2003).

    Article  Google Scholar 

  13. Markert, J. A., Danley, P. D. & Arnegard, M. E. New markers for new species: microsatellite loci and the East African cichlids. Trends Ecol. Evol. 16, 100–107 (2001).

    Article  PubMed  Google Scholar 

  14. van Oppen, M. J. H. et al. Unusually fine-scale genetic structuring found in rapidly speciating Malawi cichlid fishes. Proc. R. Soc. Lond. B 264, 1803–1812 (1997).

    Article  Google Scholar 

  15. Arnegard, M. E. et al. Population structure and colour variation of the cichlid fish Labeotropheus fuelleborni Ahl along a recently formed achipelago of rocky habitat patches in southern Lake Malawi. Proc. R. Soc. Lond. B 266, 119–130 (1999).

    Article  Google Scholar 

  16. Knight, M. E., Turner, G. F., van Oppen, M. J. H., Rico, C & Hewitt, G. M. Microsatellite DNA and sex-biased dispersal among Lake Malawi cichlids. Mol. Ecol. 8, 1521–1527 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Danley, P. D., Markert, J. A., Arnegard, M. E. & Kocher, T. D. Divergence with gene flow in the rock-dwelling cichlids of Lake Malawi. Evol. Int. J. Org. Evol. 54, 1725–1737 (2000).

    Article  CAS  Google Scholar 

  18. Fryer, G. & Iles, T. D. The Cichlid Fishes of the Great Lakes of Africa (Oliver & Boyd, Edinburgh, 1972).

    Google Scholar 

  19. Schliewen, U. et al. Genetic and ecological divergence of a monophyletic cichlid species pair under fully sympatric conditions in Lake Ejagham, Cameroon. Mol. Ecol. 10, 1471–1488 (2001). Conclusive evidence for the sympatric speciation of cichlids within the confines of a tiny crater lake.

    Article  CAS  PubMed  Google Scholar 

  20. Maynard Smith, J. Sympatric speciation. Am. Nat. 100, 637–650 (1966).

    Article  Google Scholar 

  21. Felsenstein, J. Skepticism towards Santa Rosalia, or why are there so few kinds of animals? Evolution 35, 124–138 (1981).

    Article  PubMed  Google Scholar 

  22. Kondrashov, A. S. & Kondrashov, F. A. Interactions among quantitative traits in the course of sympatric speciation. Nature 400, 351–354 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Dieckmann, U. & Doebeli, M. On the origin of species by sympatric speciation. Nature 400, 354–357 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Dominey, W. J. in Evolution of Fish Species Flocks (eds Echelle, A. A. & Kornfield, I.) 231–250 (Univ. Maine Press, Orono, 1984).

    Google Scholar 

  25. McKaye, K. R. in Cichlid Fishes: Behavior, Ecology and Evolution (ed. Keenleyside, M. H. A.) 241–257 (Chapman and Hall, London, 1991).

    Google Scholar 

  26. Lande, R. Models of speciation by sexual selection on polygenic traits. Proc. Natl Acad. Sci. USA 78, 3721–3725 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Turner, G. F. & Burrows, M. T. A model of sympatric speciation by sexual selection. Proc. R. Soc. Lond. B 260, 287–292 (1995).

    Article  Google Scholar 

  28. Payne, R. J. H. & Krakauer, D. C. Sexual selection, space and speciation. Evolution 51, 1–9 (1997).

    Article  PubMed  Google Scholar 

  29. Higashi, M., Takimoto, G. & Yamamura, N. Sympatric speciation by sexual selection. Nature 402, 523–526 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. van Doorn, G. S., Noest, A. J. & Hogeweg, P. Sympatric speciation and extinction driven by environment dependent sexual selection. Proc. R. Soc. Lond. B 265, 1915–1919 (1998).

    Article  Google Scholar 

  31. van Oppen, M. J. H. et al. Assortative mating among rock-dwelling cichlid fishes supports high estimates of species richness from Lake Malawi. Mol. Ecol. 7, 991–1001 (1998).

    Article  Google Scholar 

  32. Knight, M. E., Turner, G. F., Rico, C., van Oppen, M. J. H. & Hewitt, G. M. Microsatellite paternity analysis on captive Lake Malawi cichlids supports reproductive isolation by direct mate choice. Mol. Ecol. 7, 1605–1610 (1998). A laboratory experiment that demonstrates complete assortative mating of three sympatric species in the absence of any microhabitat or environmental cues.

    Article  Google Scholar 

  33. Seehausen, O. & van Alphen, J. J. M. The effect of male coloration on female mate choice in closely related Lake Victoria cichlids (Haplochromis nyererei complex). Behav. Ecol. Sociobiol. 42, 1–8 (1998).

    Article  Google Scholar 

  34. Knight, M. E. & Turner, G. F. Reproductive isolation among closely related Lake Malawi cichlids: can males recognize conspecific females by visual cues? Anim. Behav. 58, 761–768 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Hurst, L. D., Atlan, A. & Bengtsson, B. O. Genetic conflicts. Q. Rev. Biol. 71, 317–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Rice, W. R. & Chippindale, A. K. The evolution of hybrid infertility: perpetual coevolution between gender-specific and sexually antagonistic genes. Genetica 116, 179–188 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Palumbi, S. R. in Endless Forms: Species and Speciation (eds Howard, D. J. & Berlocher, S. H.) 271–278 (Oxford Univ. Press, New York, 1998).

    Google Scholar 

  38. Werren, J. H. & Beukeboom, L. W. Sex determination, sex ratios, and genetic conflict. Annu. Rev. Ecol. Syst. 29, 233–261 (1998)

    Article  Google Scholar 

  39. Werren, J. H. & Hatcher, M. J. Maternal–zygotic gene conflict over sex deterimination: effects of inbreeding. Genetics 155, 1469–1479 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Seehausen, O., van Alphen, J. J. M. & Lande, R. Color polymorphism and sex ratio distortion in a cichlid fish as an incipient stage in sympatric speciation by sexual selection. Ecol. Lett. 2, 367–378 (1999).

    Article  Google Scholar 

  41. Lande, R., Seehausen, O. & van Alphen, J. J. M. Mechanisms of rapid sympatric speciation by sex reversal and sexual selection in cichlid fish. Genetica 112-113, 435–443 (2001). Results from crosses among Lake Victoria cichlids stimulate new models of speciation that involve the evolution of colour patterns and the sex-determining genes.

    Article  CAS  PubMed  Google Scholar 

  42. Kocher, T. D., Lee, W. J., Sobolewska, H., Penman, D. & McAndrew, B. A genetic linkage map of a cichlid fish, the tilapia (Oreochromis niloticus). Genetics 148, 1225–1232 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Albertson, R. C., Streelman, J. T. & Kocher, T. D. Directional selection has shaped the oral jaws of Lake Malawi cichlid fishes. Proc. Natl Acad. Sci. USA 100, 5252–5257 (2003). Mapping of quantitative trait loci for jaw and tooth morphology reveals the imprint of consistent directional selection on the trophic apparatus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Albertson, R. C., Streelman, J. T. & Kocher, T. D. Genetic basis of adaptive shape differences in the cichlid head. J. Hered. 94, 291–301 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Wilson, J. & Tucker, A. S. Fgf and Bmp signals repress the expression of Bapx1 in the mandibular mesenchyme and control the position of the developing jaw joint. Dev. Biol. 266, 138–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Terai, Y., Morikawa, N. & Okada, N. The evolution of the pro-domain of bone morphogenetic protein 4 (Bmp4) in an explosively speciated lineage of East African cichlid fishes. Mol. Biol. Evol. 19, 1628–1632 (2002).

    Article  PubMed  Google Scholar 

  47. Streelman, J. T., Webb, J. F., Albertson, R. C. & Kocher, T. D. The cusp of evolution and development: a model of cichlid tooth shape diversity. Evol. Devel. 5, 600–608 (2003).

    Article  CAS  Google Scholar 

  48. Couldridge, V. C. K. & Alexander, G. J. Color patterns and species recognition in four closely related species of Lake Malawi cichlid. Behav. Ecol. 13, 59–64 (2002).

    Article  Google Scholar 

  49. Streelman, J. T., Albertson, R. C. & Kocher, T. D. Genome mapping of the orange blotch color pattern in cichlid fishes. Mol. Ecol. 12, 2465–2471 (2003). Comparative mapping among fish species identified candidate genes for the OB polymorphism that is common among species from lakes Malawi and Victoria.

    Article  CAS  PubMed  Google Scholar 

  50. Terai, Y., Morikawa, N., Kawakami, K. & Okada, N. Accelerated evolution of the surface amino acids in the WD-repeat domain encoded by the hagoromo gene in an explosively speciated lineage of East African cichlid fishes. Mol. Biol. Evol. 19, 574–578 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Terai, Y., Morikawa, N., Kawakami, K. & Okada, N. The complexity of alternative splicing of hagoromo mRNAs is increased in an explosively speciated lineage in East African cichlids. Proc. Natl Acad. Sci. USA 100, 12798–12803 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carleton, K. L., Harosi, F. I. & Kocher, T. D. Visual pigments of African cichlid fishes: Evidence for ultraviolet vision from microspectrophotometry and DNA sequences. Vision Res. 40, 879–890 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Carleton, K. L. & Kocher, T. D. Cone opsin genes of African cichlid fishes: tuning spectral sensitivity by differential gene expression. Mol. Biol. Evol. 18, 1540–1550 (2001). Expression analysis reveals the genetic basis for the dramatic differences in visual sensitivity among Lake Malawi cichlids.

    Article  CAS  PubMed  Google Scholar 

  54. Terai, Y., Mayer, W. E., Klein, J., Tichy, H. & Okada, N. The effect of selection on a long wavelength-sensitive (LWS) opsin gene of Lake Victoria cichlid fishes. Proc. Natl Acad. Sci. USA 99, 15501–15506 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sugawara, T., Terai, Y. & Okada, N. Natural selection of the rhodopsin gene during the adaptive radiation of East African Great Lakes cichlid fishes. Mol. Biol. Evol. 19, 1807–1811 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Seehausen, O., van Alphen, J. J. M. & Witte, F. Cichlid fish diversity threatened by eutrophication that curbs sexual selection. Science 277, 1808–1811 (1997).

    Article  CAS  Google Scholar 

  57. Feder, M. E., & Mitchell-Olds, T. Evolutionary and ecological functional genomics. Nature Rev. Genet. 4, 649–655 (2003).

    Article  CAS  Google Scholar 

  58. Nachman, M. W., Hoekstra, H. E., D'Agostino, S. L. The genetic basis of adaptive melanism in pocket mice. Proc. Natl Acad. Sci. USA 100, 5268–5273 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Peichel, C. L. et al. The genetic architecture of divergence between threespine stickleback species. Nature 414, 901–905 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Thorgaard, G. H. et al. Status and opportunities for genomics research with rainbow trout. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. 133, 609–646 (2002).

    Article  Google Scholar 

  61. Yamamoto, Y., Espinasa, L, Stock, D. W. & Jeffery, W. R. Development and evolution of craniofacial patterning is mediated by eye-dependent and-independent processes in the cavefish Astyanax. Evol. Dev. 5, 435–446 (2003).

    Article  PubMed  Google Scholar 

  62. Gavrilets, S. Perspective: models of speciation: what have we learned in 40 years? Evolution 57, 2197–2215 (2003).

    Article  PubMed  Google Scholar 

  63. Hey, J., Won, Y. -J., Sivasundar, A., Nielsen, R. & Markert, J. A. Using nuclear haplotypes with microsatellites to study gene flow between recently separated populations. Mol. Ecol. (in the press). A novel analysis of nuclear haplotypes is used to estimate population genetic parameters during speciation of Lake Malawi cichlids.

  64. Allender, C. J., Seehausen, O., Knight, M. E., Turner, G. F. & Maclean, N. Divergent selection during speciation of Lake Malawi cichlid fishes inferred from parallel radiations in nuptial coloration. Proc. Natl Acad. Sci. USA 100, 14074–14079 (2003). A phylogeny based on amplified restriction fragment polymorphisms demonstrates the repeated parallel evolution of male colour patterns in Lake Malawi.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Templeton, A. R. Mechanisms of speciation — a population genetic approach. Annu. Rev. Ecol. Syst. 12, 23–48 (1981).

    Article  Google Scholar 

  66. Panhuis, T. M., Butlin, R., Zuk, M. & Tregenza, T. Sexual selection and speciation. Trends Ecol. Evol. 16, 364–371 (2001).

    Article  PubMed  Google Scholar 

  67. Meyer, A. Phylogenetic relationships and evolutionary processes in East African cichlid fishes. Trends Ecol. Evol. 8, 279–284 (1993).

    Article  CAS  PubMed  Google Scholar 

  68. Takahashi, K., Terai, T., Nishida, M. & Okada, N. Phylogenetic relationships and ancient incomplete lineage sorting among cichlid fishes in Lake Tanganyika as revealed by analysis of the insertion of retroposons. Mol. Biol. Evol. 18, 2057–2066 (2001). Unique insertions of retroposons are used to reconstruct the history of Tanganyikan cichlids, and reveal the incomplete fixation of alleles during speciation in the early history of the lake.

    Article  CAS  PubMed  Google Scholar 

  69. Salzburger, W., Meyer, A., Baric, S., Verheyen, E. & Sturmbauer, C. Phylogeny of the Lake Tanganyika cichlid species flock and its relationship to the Central and East African haplochromine cichlid fish faunas. Syst. Biol. 51, 113–135 (2002). One of the most complete analyses of mitochondrial DNA sequences to reconstruct the history of the East African radiations.

    Article  PubMed  Google Scholar 

  70. Meyer, A., Kocher, T. D., Basasibwaki, P. & Wilson, A. C. Monophyletic origin of Lake Victoria cichlid fishes suggested by mitochondrial DNA sequences. Nature 347, 550–553 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. Verheyen, E., Salzburger, W., Snoeks, J. & Meyer, A. Origin of the superflock of cichlid fishes from Lake Victoria, East Africa. Science 300, 325–329 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Moran, P. & Kornfield, I. Retention of an ancestral polymorphism in the mbuna species flock (Teleostei: Cichlidae) of Lake Malawi. Mol. Biol. Evol. 10, 1015–1029 (1993).

    CAS  Google Scholar 

  73. Nagl, S., Tichy, H., Mayer, W. E., Takahata, N. & Klein, J. Persistence of neutral polymorphisms in Lake Victoria cichlid fish. Proc. Natl Acad. Sci. USA 95, 14238–14243 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Figueroa, F. et al. Mhc class II B gene evolution in East African cichlid fishes. Immunogenetics 51, 556–575 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Albertson, R. C., Markert, J. A., Danley, P. D. & Kocher, T. D. Phylogeny of a rapidly evolving clade: the cichlid fishes of Lake Malawi, East Africa. Proc. Natl Acad. Sci. USA 96, 5107–5110.

  76. Seehausen, O. et al. Nuclear markers reveal unexpected genetic variation and a Congolese/Nilotic origin of the Lake Victoria cichlid species flock. Proc. R. Soc. Lond. B 270, 129–137 (2003).

    Article  Google Scholar 

  77. Lee, B. -Y., Penman, D. J. & Kocher, T. D. Identification of a sex-determining region in Nile tilapia (Oreochromis niloticus) using bulked segregant analysis. Anim. Genet. 34, 379–383.

  78. Lee, B. -Y., Hulata, G. & Kocher, T. D. Two unlinked loci controlling the sex of blue tilapia (Oreochromis aureus). Heredity (in the press).

Download references

Acknowledgements

I thank R.C. Albertson, K. Carleton, M. Kidd, O. Seehausen, J.T. Streelman and the anonymous reviewers for helpful discussions and comments. My work on cichlid fishes has been supported by the US National Science Foundation and the US Department of Agriculture.

Author information

Authors and Affiliations

  1. Hubbard Center for Genome Studies, University of New Hampshire, Suite 400, Environmental Technology Building, 35 Colovos Road, Durham, 03824, New Hampshire, USA

    Thomas D. Kocher

Authors
  1. Thomas D. Kocher
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Thomas D. Kocher's laboratory

Cichlid Genome Consortium

Cichlid fishes of Lake Malawi

Glossary

SEXUAL ANTAGONISM

Where an allele is favoured in one sex and selected against in another.

ALLOPATRIC SPECIATION

Speciation that involves the differentiation of geographically separate populations.

SEXUAL SELECTION

Selection among individuals of one sex that is exerted through competition for mates, or the mating preferences of the opposite sex.

PHYLOGENY

The evolutionary relationships of a group of organisms, which are often depicted as a tree diagram.

TROPHIC MORPHOLOGY

The morphological characteristics of an animal that relate to its intake of food.

LINKAGE DISEQUILIBRIUM

(LD). A measure of genetic associations between alleles at different loci, which indicates whether certain allelic combinations are more common than expected.

FISHER'S PROCESS

A process of runaway evolution of male traits and female mating preferences under sexual selection, which Ronald A. Fisher is credited with recognizing.

NICHE DIFFERENTIATION

The tendency for co-existing species to differ in their niche requirements.

MICROPYLE

An opening in the egg capsule through which spermatozoa enter.

POLYSPERMY

The entry of several sperm into one egg.

CYTOPLASMIC FACTORS

Genes in host organelles such as mitochondria, or in intracellular parasites such as Wolbachia, that are typically passed from mother to offspring through the cytoplasm.

MEIOTIC DRIVE

The preferential transmission of one gamete genotype over another genotype, in which the genotypes in question might derive from the same meiosis.

GAMETIC IMPRINTING

The persistent differential methylation of parental genes that results in the expression of the allele from only one parent in the offspring.

CONSERVED SYNTENY

Conservation of the linkage relationship among genes between two species.

LINKAGE DISEQUILIBRIUM MAPPING

The analysis of single-nucleotide-polymorphism alleles in population-based studies to identify loci that are associated with a particular phenotype.

ASSOCIATION STUDIES

An approach to gene mapping that looks for associations between a particular phenotype and allelic variation.

COALESCENT HISTORY

The genealogical history of alleles within a population.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kocher, T. Adaptive evolution and explosive speciation: the cichlid fish model. Nat Rev Genet 5, 288–298 (2004). https://doi.org/10.1038/nrg1316

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1316

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