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Pleiotropic scaling of gene effects and the ‘cost of complexity’


As perceived by Darwin, evolutionary adaptation by the processes of mutation and selection is difficult to understand for complex features that are the product of numerous traits acting in concert, for example the eye or the apparatus of flight. Typically, mutations simultaneously affect multiple phenotypic characters. This phenomenon is known as pleiotropy. The impact of pleiotropy on evolution has for decades been the subject of formal analysis1,2,3,4,5,6. Some authors have suggested that pleiotropy can impede evolutionary progress (a so-called ‘cost of complexity’5). The plausibility of various phenomena attributed to pleiotropy depends on how many traits are affected by each mutation and on our understanding of the correlation between the number of traits affected by each gene substitution and the size of mutational effects on individual traits. Here we show, by studying pleiotropy in mice with the use of quantitative trait loci (QTLs) affecting skeletal characters, that most QTLs affect a relatively small subset of traits and that a substitution at a QTL has an effect on each trait that increases with the total number of traits affected. This suggests that evolution of higher organisms does not suffer a ‘cost of complexity’ because most mutations affect few traits and the size of the effects does not decrease with pleiotropy.

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Figure 1: Distribution of QTL effects on 70 skeletal traits in the mouse.


  1. Fisher, R. A. The Genetical Theory of Natural Selection (Clarendon, Oxford, 1930)

    Book  Google Scholar 

  2. Rechenberg, I. Evolutionsstrategie: Optimierung technischer Systeme nach Prinzipien der biologischen Evolution (Fromman-Holzboog, Stuttgart, 1973)

    Google Scholar 

  3. Turelli, M. Effects of pleiotropy on predictions concerning mutation-selection balance for polygenic traits. Genetics 111, 165–195 (1985)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Wagner, G. P. The influence of variation and developmental constraints on the rate of multivariate phenotypic evolution. J. Evol. Biol. 1, 45–66 (1988)

    Article  Google Scholar 

  5. Orr, H. A. Adaptation and the cost of complexity. Evolution Int. J. Org. Evolution 54, 13–20 (2000)

    Article  CAS  Google Scholar 

  6. Wingreen, N. S., Miller, J. & Cox, E. C. Scaling of mutational effects in models of pleiotropy. Genetics 164, 1221–1228 (2003)

    PubMed  PubMed Central  Google Scholar 

  7. Chai, C. K. Analysis of quantitative inheritance of body size in mice II: gene action and segregation. Genetics 41, 165–178 (1956)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Eppig, J. T., Bult, C. J., Kadin, J. A., Richardson, J. E. & Blake, J. A. and the members of the Mouse Genome Database Group. The mouse genome data base (MGD): from genes to mice – a community resource for mouse biology. Nucleic Acids Res. 33, D471–D475 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. Kenney-Hunt, J. P. et al. Pleiotropic patterns of quantitative trait loci for seventy murine skeletal traits. Genetics (in the press)

  10. Knott, S. A. & Haley, C. S. Multitrait least squares for quantitative trait loci detection. Genetics 156, 899–911 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu, S. Theoretical basis of the Beavis effect. Genetics 165, 2259–2268 (2003)

    PubMed  PubMed Central  Google Scholar 

  12. Wagner, G. P. Multivariate mutation-selection balance with constrained pleiotropic effects. Genetics 122, 223–234 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Waxman, D. & Peck, J. R. Pleiotropy and preservation of perfection. Science 279, 1210–1213 (1998)

    Article  CAS  ADS  PubMed  Google Scholar 

  14. Waddington, C. H. The Strategy of Genes (Macmillan, New York, 1957)

    Google Scholar 

  15. Hermisson, J. & Wagner, G. P. The population genetic theory of hidden variation and genetic robustness. Genetics 168, 2271–2284 (2004)

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wagner, G. P. & Altenberg, L. Complex adaptation and the evolution of evolvability. Evolution Int. J. Org. Evolution 50, 967–976 (1996)

    Article  Google Scholar 

  17. Hansen, T. F. Is modularity necessary for evolvability? Remarks on the relationship between pleiotropy and evolvability. Biosystems 69, 83–94 (2003)

    Article  PubMed  Google Scholar 

  18. Wagner, G. P., Pavlicev, M. & Cheverud, J. M. The road to modularity. Nature Rev. Genet. 8, 921–931 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. Welch, J. J. & Waxman, D. Modularity and the cost of complexity. Evolution Int. J. Org. Evolution 57, 1723–1734 (2003)

    Article  Google Scholar 

  20. Martin, G. & Lenormand, T. A general multivariate extension of Fisher’s geometrical model and the distribution of mutation fitness effects across species. Evolution Int. J. Org. Evolution 60, 893–907 (2006)

    Article  Google Scholar 

  21. Cheverud, J. M. et al. Quantitative trait loci for murine growth. Genetics 142, 1305–1319 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Vaughn, T. T. et al. Mapping quantitative trait loci for murine growth: a closer look at genetic architecture. Genet. Res. 74, 313–322 (1999)

    Article  CAS  PubMed  Google Scholar 

  23. Cheverud, J. M. et al. Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice. Mamm. Genome 12, 3–12 (2001)

    Article  CAS  PubMed  Google Scholar 

  24. Haley, C. S. & Knott, S. A. A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69, 315–324 (1992)

    Article  CAS  PubMed  Google Scholar 

  25. Cheverud, J. M. A simple correction for multiple comparisons in interval mapping genome scans. Heredity 87, 52–58 (2001)

    Article  CAS  PubMed  Google Scholar 

  26. Ehrich, T. H. et al. Pleiotropic effects on mandibular morphology I: developmental morphological integration and differential dominance. J. Exp. Zool. B 296, 58–78 (2003)

    Article  Google Scholar 

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We thank A. Pyle, A. Kondrashov and B. Walsh for suggestions that have improved this manuscript. We thank the members of the Wagner and Cheverud laboratories for critical discussion. J.P. and D.W. thank members of the evolution group at Sussex. J.M.C. is funded by the National Institutes of Health and the National Science Foundation (NSF), G.P.W. acknowledges funding from the NSF, the Humboldt Foundation and the John Templeton Foundation, M.P. is funded by the Austrian Science Foundation (FWF) Fellowship, and the work of D.W. was supported by the Leverhulme Trust.

Author Contributions G.P.W. conceived this study, participated in the statistical analysis and wrote the manuscript. J.P.K.-H. collected the morphological data and performed the QTL analysis. M.P. did the statistical analyses. J.M.C. was responsible for generating the mouse populations and the genotype data used in the original mapping and advised on the pleiotropic scaling analysis. J.P. and D.W. performed a theoretical analysis of the scaling of trait effects with pleiotropy. All authors participated in the preparation of the manuscript.

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Correspondence to Günter P. Wagner or James M. Cheverud.

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The file contains Supplementary Figures S1-S4 with Legends, Supplementary Table T1 and Supplementary Notes with additional references. (PDF 356 kb)

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Wagner, G., Kenney-Hunt, J., Pavlicev, M. et al. Pleiotropic scaling of gene effects and the ‘cost of complexity’. Nature 452, 470–472 (2008).

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