Review Article | Published:

The genetic theory of adaptation: a brief history

Nature Reviews Genetics volume 6, pages 119127 (2005) | Download Citation



Theoretical studies of adaptation have exploded over the past decade. This work has been inspired by recent, surprising findings in the experimental study of adaptation. For example, morphological evolution sometimes involves a modest number of genetic changes, with some individual changes having a large effect on the phenotype or fitness. Here I survey the history of adaptation theory, focusing on the rise and fall of various views over the past century and the reasons for the slow development of a mature theory of adaptation. I also discuss the challenges that face contemporary theories of adaptation.

Key points

  • Early evolutionists believed that the genetic basis of adaptation was micromutational.

  • This view was supported by Ronald Fisher's classical mathematical analysis (of 1930) of his 'geometric model' of adaptation.

  • Beginning in the 1980s, studies of quantitative trait loci and microbial experimental evolution revealed that adaptation sometimes involves a modest number of genes, some of which have surprisingly large effects. These experimental findings pose a serious challenge to evolutionary theory.

  • So far, phenotype-based and DNA sequence-based models of adaptation have yielded surprisingly similar results, indicating the possibility of a robust theory of adaptation.

  • Phenotypic models of adaptation show that the genes that cause adaptation should have approximately exponentially distributed effects; that is, involve many genes that have small effect and a few genes that have large effect.

  • DNA sequence models of adaptation indicate that adaptation should involve mutations of relatively large fitness effects and that adaptation is characterized by a pattern of diminishing returns, in which early substitutions have large fitness effects and later ones have smaller effects.

  • Current theories of adaptation adequately explain certain qualitative patterns that characterize genetic data on adaptation; however, it is not yet clear if these theories can explain these data quantitatively.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.


  1. 1.

    The Genetical Theory of Natural Selection (Oxford Univ. Press, Oxford, 1930). One of the founding documents of modern evolutionary biology. It includes Fisher's classical discussions of his geometric model of adaptation.

  2. 2.

    The Origin of Species (J. Murray, London, 1859).

  3. 3.

    The Growth of Biological Thought (Harvard Univ. Press, Cambridge, Massachusetts, 1982).

  4. 4.

    (ed.) Evolution Now: a Century After Darwin (W. H. Freeman and Co., San Francisco, 1982).

  5. 5.

    Mathematical contributions to the theory of evolution: on the law of ancestral heredity. Proc. R. Soc. Lond. 62, 386–412 (1898).

  6. 6.

    Attempt to measure the death-rate due to the selective destruction of Carcinus moenas with respect to a particular dimension. Proc. R. Soc. Lond. 58, 360–379 (1895).

  7. 7.

    The Origins of Theoretical Population Genetics (Univ. Chicago Press, Chicago, 1971).

  8. 8.

    Evolution and Adaptation (Macmillan, New York, 1903).

  9. 9.

    Mendel's Principles of Genetics (Cambridge Univ. Press, Cambridge, 1913).

  10. 10.

    Mimicry in Butterflies (Cambridge Univ. Press, Cambridge, 1915).

  11. 11.

    Fisher's evolutionary faith and the challenge of mimicry. Oxford Surv. Evol. Biol. 2, 159–196 (1985).

  12. 12.

    in Darwin and Modern Science (ed. Seward, A. C.) 85–101 (Cambridge Univ. Press, Cambridge, 1909).

  13. 13.

    The correlations between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52, 399–433 (1918).

  14. 14.

    The Mathematical Theory of Quantitative Genetics (Oxford Univ. Press, Oxford, 1980).

  15. 15.

    & Evolutionary quantitative genetics: how little do we know? Annu. Rev. Genetics 23, 337–370 (1989).

  16. 16.

    in The Probabilistic Revolution Vol. 2 (eds. Kruger, L., Gigerenzer, G. & Morgan, M. S.) 313–354 (The MIT Press, Cambridge, Massachusetts, 1987).

  17. 17.

    Genetics and the Origin of Species (Columbia Univ. Press, New York, 1937).

  18. 18.

    Eugenics, Genetics and the Family: Proceedings of the Second International Congress of Eugenics Vol. 1 (ed. History, A. M.) (William and Wilkens, Baltimore, 1923).

  19. 19.

    in The New Systematics (ed. Huxley, J. S.) 185–268 (Clarendon Press, Oxford, 1940).

  20. 20.

    The Darwinian and modern conceptions of natural selection. Proc. Am. Phil. Soc. 93, 459–470 (1949).

  21. 21.

    Polygenic inheritance and natural selection. Biol. Rev. 18, 32–64 (1943).

  22. 22.

    Biometrical Genetics (Dover, New York, 1949).

  23. 23.

    Evolution as a Process (Unwin Bros, Woking; London, 1954).

  24. 24.

    Evolution, the Modern Synthesis (George Allen & Unwin, London, 1942).

  25. 25.

    & The genetics of adaptation revisited. Am. Nat. 140, 725–742 (1992).

  26. 26.

    Mapping polygenes. Annu. Rev. Genet. 27, 205–233 (1993).

  27. 27.

    & Introduction to Quantitative Genetics (Longman, Harlow, England, 1996).

  28. 28.

    & QTL analysis in plants; where are we now? Heredity 80, 137–142 (1998).

  29. 29.

    The genetics of species differences. Trends Ecol. Evol. 16, 343–350 (2001).

  30. 30.

    Quantitative trait loci in Drosophila. Nature Rev. Genet. 2, 11–20 (2001).

  31. 31.

    & Profiles of adaptation in two similar viruses. Genetics 159, 1393–1404 (2001).

  32. 32.

    et al. Exceptional convergent evolution in a virus. Genetics 147, 1497–1507 (1997).

  33. 33.

    , , , & Different trajectories of parallel evolution during viral adaptation. Science 285, 422–424 (1999).

  34. 34.

    , & Genetic architecture of thermal adaptation in Escherichia coli. Proc. Natl Acad. Sci. USA 98, 525–530 (2001).

  35. 35.

    et al. Mode of selection and experimental evolution of antifungal drug resistance in Saccharomyces cerevisiae. Genetics 163, 1287–1298 (2003).

  36. 36.

    Darwinian evolution of mutations. Eugen. Rev. 14, 31–34 (1922).

  37. 37.

    The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, 1983).

  38. 38.

    The population genetics of adaptation: the distribution of factors fixed during adaptive evolution. Evolution 52, 935–949 (1998). A theoretical study of the genetic basis of phenotypic evolution using Fisher's geometric model of adaptation. This study argues that previous claims about adaptation based on Fisher's model were partly mistaken.

  39. 39.

    The evolutionary genetics of adaptation: a simulation study. Genet. Res. 74, 207–214 (1999).

  40. 40.

    The geometry of natural selection. Nature 395, 751–752 (1998).

  41. 41.

    & Understanding quantitative genetic variation. Nature Rev. Genet. 3, 11–21 (2002).

  42. 42.

    , & Imperfect genes, Fisherian mutation and the evolution of sex. Genetics 145, 1171–1199 (1997).

  43. 43.

    A geometric model for the evolution of development. J. Theor. Biol. 143, 319–342 (1990).

  44. 44.

    & Compensatory nearly neutral mutations: selection without adaptation. J. Theor. Biol. 182, 303–309 (1996).

  45. 45.

    & Towards a theory of evolutionary adaptation. Genetica 102/103, 525–533 (1998).

  46. 46.

    & Compensating for our load of mutations: freezing the meltdown of small populations. Evolution 54, 1467–1479 (2000).

  47. 47.

    The role of hybridization in evolution. Mol. Ecol. 10, 551–568 (2001).

  48. 48.

    Adaptation and the cost of complexity. Evolution 54, 13–20 (2000).

  49. 49.

    & Modularity and the cost of complexity. Evolution 57, 1723–1734 (2003).

  50. 50.

    The Scientist Speculates: an Anthology of Partly-Baked Ideas (ed. Good, I. J.) 252–256 (Basic Books, New York, 1962). This introduced the idea of adaptation through a 'sequence space'. Although Maynard Smith considered protein spaces, his ideas had a key role in later thinking about adaptative walks through DNA sequence spaces.

  51. 51.

    Natural selection and the concept of a protein space. Nature 225, 563–564 (1970).

  52. 52.

    Evolutionary rate at the molecular level. Nature 217, 624–626 (1968).

  53. 53.

    & Non-Darwinian evolution: random fixation of selectively neutral mutations. Science 164, 788–798 (1969).

  54. 54.

    Molecular Evolution and Polymorphism (ed. Kimura, M.) 148–167 (Natl Inst. Genet., Mishima, 1977).

  55. 55.

    Model of effectively neutral mutations in which selective constraint is incorporated. Proc. Natl Acad. Sci. USA 76, 3440–3444 (1979).

  56. 56.

    The nearly neutral theory of molecular evolution. Annu. Rev. Ecol. Syst. 23, 263–286 (1992).

  57. 57.

    & The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist program. Proc. R. Soc. Lond. B 205, 581–598 (1979).

  58. 58.

    & Towards a general theory of adaptive walks on rugged landscapes. J. Theor. Biol. 128, 11–45 (1987). This paper introduced the idea of adaptation over fitness landscapes of varying ruggedness. Although it largely focused on 'random' landscapes, the paper gave rise to a large literature on landscapes of different ruggedness.

  59. 59.

    , & in Theoretical Immunology: Part One (ed. Perelson, A. S.) 349–382 (Addison-Wesley, New York, 1988).

  60. 60.

    The Origins of Order (Oxford Univ. Press, New York, 1993).

  61. 61.

    A more rigorous derivation of some properties of uncorrelated fitness landscapes. J. Theor. Biol. 134, 125–129 (1988).

  62. 62.

    Correlated and uncorrelated fitness landscapes and how to tell the difference. Biol. Cybern. 63, 325–336 (1990).

  63. 63.

    Local properties of Kauffman's N-k model: a tunably rugged energy landscape. Phys. Rev. A 44, 6399–6413 (1991).

  64. 64.

    & Protein evolution on rugged landscapes. Proc. Natl Acad. Sci. USA 86, 6191–6195 (1989).

  65. 65.

    , & Evolutionary walks on rugged landscapes. SIAM J. Appl. Math. 51, 799–827 (1991).

  66. 66.

    & Evolution in a rugged fitness landscape. Phys. Rev. A 46, 6714–6723 (1992).

  67. 67.

    et al. RNA folding and combinatory landscapes. Phys. Rev. E 47, 2083–2099 (1993).

  68. 68.

    & Random field models for fitness landscapes. J. Math. Biol. 38, 435–478 (1999).

  69. 69.

    & in 1993 Lectures in Complex Systems (eds Nadel, L. & Stein, D. L.) 43–86 (Addison-Wesley, Reading, Massachusetts, 1995).

  70. 70.

    Evolution in Mendelian populations. Genetics 16, 97–159 (1931).

  71. 71.

    The roles of mutation, inbreeding, crossbreeding, and selection in evolution. Proc. Sixth Intl Cong. Genet. 1, 356–366 (1932).

  72. 72.

    Fitness Landscapes and the Origin of Species (Princeton Univ. Press, Princeton, 2004).

  73. 73.

    & Protein evolution on partially correlated landscapes. Proc. Natl Acad. Sci. USA 92, 9657–9661 (1995).

  74. 74.

    in Emerging Synthesis in Science: Proceedings of the Founding Workshop of the Santa Fe Institute (ed. Pines, D.) (Santa Fe Inst., Santa Fe, 1985).

  75. 75.

    A simple stochastic gene substitution model. Theor. Popul. Biol. 23, 202–215 (1983).

  76. 76.

    Molecular evolution over the mutational landscape. Evolution 38, 1116–1129 (1984). This is Gillespie's most extensive discussion of the use of extreme value theory in the study of molecular evolution.

  77. 77.

    The Causes of Molecular Evolution (Oxford Univ. Press, Oxford, 1991).

  78. 78.

    Statistics of Extremes (Columbia Univ. Press, New York, 1958).

  79. 79.

    , & Extremes and Related Properties of Random Sequences and Processes (Springer, New York, 1983).

  80. 80.

    (ed.) Extremes and Integrated Risk Management (Risk Books, London, 2000).

  81. 81.

    Biological Evolution and Statistical Physics (eds Lassig, M. & Valleriani, A.) 183–204 (Springer, Berlin, 2002).

  82. 82.

    Breaking records and breaking boards. Am. Math. Monthly 85, 2–26 (1978).

  83. 83.

    , & Records (John Wiley and Sons, New York, 1998).

  84. 84.

    Is the population size of a species relevant to its evolution? Evolution 55, 2161–2169 (2003).

  85. 85.

    Natural selection and the molecular clock. Mol. Biol. Evol. 3, 138–155 (1986).

  86. 86.

    Molecular evolution and the neutral allele theory. Oxford Surv. Evol. Biol. 4, 10–37 (1989).

  87. 87.

    The rhythm of microbial adaptation. Nature 413, 299–302 (2001).

  88. 88.

    The distribution of fitness effects among beneficial mutations. Genetics 163, 1519–1526 (2003).

  89. 89.

    , & Fitness effects of fixed benefical mutations in microbial populations. Curr. Biol. 12, 1040–1045 (2002).

  90. 90.

    The population genetics of adaptation: the adaptation of DNA sequences. Evolution 56, 1317–1330 (2002). This paper brought the extreme value theory to bear on several key questions in the study of DNA sequence adaptation.

  91. 91.

    The probability of parallel adaptation. Evolution (in the press).

  92. 92.

    Theories of adaptation: what they do and don't say. Genetica (in the press).

  93. 93.

    & Fitness effects of advantageous mutations in evolving Escherichia coli populations. Proc. Natl Acad. Sci. USA 98, 1113–1117 (2001).

  94. 94.

    , & The distribution of fitness effects caused by single-nucleotide substitutions in an RNA virus. Proc. Natl Acad. Sci. USA 101, 8396–8401 (2004).

  95. 95.

    et al. Genetic analysis of a morphological shape difference in the male genitalia of Drosophila simulans and D. mauritiana. Genetics 142, 1129–1145 (1996).

  96. 96.

    The Genetical Theory of Natural Selection: a Complete Variorum Edition (Oxford Univ. Press, Oxford, 2000).

  97. 97.

    et al. The genetic architecture of parallel armor plate reduction in threespine sticklebacks. PLoS Biol. 2, e109 (2004).

  98. 98.

    et al. Parallel genetic basis for repeated evolution of armor loss in Alaskan threespine stickleback populations. Proc. Natl Acad. Sci. USA 101, 6050–6055 (2004).

  99. 99.

    et al. Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428, 717–723 (2004). Experimental analysis that identified a candidate gene, Pitx1, that has an important role in the morphological adaptation of marine sticklebacks to lake environments.

  100. 100.

    & Divergence of larval morphology between Drosophila sechellia and its sibling species caused by cis-regulatory evolution of ovo/shaven-baby. Proc. Natl Acad. Sci. USA 97, 4530–4534 (2000).

  101. 101.

    & Of genes and genomes and the origin of maize. Trends Genet. 14, 327–332 (1998).

  102. 102.

    , , , & The limits of selection during maize domestication. Nature 398, 236–239 (1999).

  103. 103.

    The genetics of maize evolution. Annu. Rev. Genet. 38, 37–59 (2004). A comprehensive and up-to-date review of Doebley's classical studies of the genetic basis of maize domestication.

  104. 104.

    , , & Genetic mapping of floral traits associated with reproductive isolation in monkeyflowers (Mimulus). Nature 376, 762–765 (1995).

  105. 105.

    , , , & Quantitative trait loci affecting differences in floral morphology between two species of Monkeyflower (Mimulus). Genetics 149, 367–382 (1998). An early and important QTL analysis that implicates the major genes in the natural adaptation of plant species to their pollinators.

  106. 106.

    & Allele substitution at a flower colour locus produces a pollinator shift in monkeyflowers. Nature 426, 176–178 (2003).

  107. 107.

    Ronald Fisher and the development of evolutionary theory. II. Influences of new variation on evolutionary process. Oxford Surv. Evol. Biol. 4, 212–264 (1987).

  108. 108.

    & Detecting the undetected: estimating the total number of loci underlying a trait in QTL analyses. Genetics 156, 2093–2107 (2000).

  109. 109.

    Order Statistics (John Wiley and Sons, New York, 1970).

  110. 110.

    Estimation of parameters and large quantiles based on the kth largest observations. J. Am. Stat. Assoc. 73, 812–815 (1978).

  111. 111.

    & Speciation (Sinauer Associates Inc., Sunderland, Massachusetts, 2004).

Download references


This work was supported by a grant from the US National Institutes of Health.

Author information


  1. Department of Biology, University of Rochester, Rochester, New York 14627, USA.

    • H. Allen Orr


  1. Search for H. Allen Orr in:

Competing interests

The author declares no competing financial interests.



Allelic variation that is currently segregating within a population; as opposed to alleles that appear by new mutation events.


A quantity that is proportional to the mean number of viable, fertile progeny produced by a genotype.


A type of genetic mapping that uses chromosomal deletions to 'uncover' recessive alleles that affect a trait.


The use of genetically defined knockout mutations to identify loci that affect a trait.


An approach to the study of phenotypes that emphasizes quantitative measurements (such as of body size) and statistical analysis.


A trait (such as body size) that varies smoothly (continuously) in magnitude; as opposed to discrete characters.


Any non-additive interaction between two or more mutations at different loci, such that their combined effect on a phenotype deviates from the sum of their individual effects.


The part of the total genetic variation that is due to the main (or additive) effects of alleles on a phenotype; as opposed to the dominance and epistatic variances. The additive variance determines the degree of resemblance between relatives and therefore the response to selection.


(QTL). A mapped chromosomal region that has a detectable effect on a phenotypic difference between two populations or species. A QTL does not necessarily correspond to a single gene, but can reflect several linked genes.


An experimental approach that involves the 'real time' adaptation of microbes (typically bacteria, phage or yeast) to defined laboratory conditions.


Evolution in which a second substitution compensates for the deleterious effects of an earlier substitution.


The decrease in population fitness below its ideal value owing to recurrent deleterious mutation.


The idea that organisms are broken developmentally into roughly independent modules, such that mutations affecting traits in one module do not affect traits in other modules.


A largely verbal theory of evolution which maintains that the interaction between natural selection, genetic drift and migration is more important that the action of any single force. Sewall Wright argued that this theory helped to explain how species could effectively search for the global, and not merely local, optimum.


An increase in the affinity of an antibody for an antigen which is seen as an immune response improves.


Magnetic objects that are disordered and in which adjacent dipoles can either 'point' in the same direction or in opposite directions.


The empirical finding that a particular type of protein or DNA sequence evolves at a nearly constant rate through time.


A simple statistical process in which there is a small and constant probability of change during each short interval of time.

About this article

Publication history