Skip to main content

Thank you for visiting 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.

Metabolic trade-offs and the maintenance of the fittest and the flattest


How is diversity maintained? Environmental heterogeneity is considered to be important1, yet diversity in seemingly homogeneous environments is nonetheless observed2. This, it is assumed, must either be owing to weak selection, mutational input or a fitness advantage to genotypes when rare1. Here we demonstrate the possibility of a new general mechanism of stable diversity maintenance, one that stems from metabolic and physiological trade-offs3. The model requires that such trade-offs translate into a fitness landscape in which the most fit has unfit near-mutational neighbours, and a lower fitness peak also exists that is more mutationally robust. The ‘survival of the fittest’ applies at low mutation rates, giving way to ‘survival of the flattest’4,5,6 at high mutation rates. However, as a consequence of quasispecies-level negative frequency-dependent selection and differences in mutational robustness we observe a transition zone in which both fittest and flattest coexist. Although diversity maintenance is possible for simple organisms in simple environments, the more trade-offs there are, the wider the maintenance zone becomes. The principle may be applied to lineages within a species or species within a community, potentially explaining why competitive exclusion need not be observed in homogeneous environments. This principle predicts the enigmatic richness of metabolic strategies in clonal bacteria7 and questions the safety of lethal mutagenesis8,9 as an antimicrobial treatment.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Maintenance of the fittest and flattest with known parameter values.
Figure 2: The maintenance of the fittest and the flattest is not a simple mutation–selection equilibrium.
Figure 3: Quasispecies negative frequency-dependent selection.


  1. 1

    Chesson, P. Mechanisms of maintenance of species diversity. Annu. Rev. Ecol. Syst. 31, 343–366 (2000)

    Article  Google Scholar 

  2. 2

    Maharjan, R., Seeto, S., Notley-McRobb, L. & Ferenci, T. Clonal adaptive radiation in a constant environment. Science 313, 514–517 (2006)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Gudelj, I., Beardmore, R. E., Arkin, S. S. & MacLean, R. C. Constraints on microbial metabolism drive evolutionary diversification in homogeneous environments. J. Evol. Biol. 20, 1882–1889 (2007)

    CAS  Article  Google Scholar 

  4. 4

    Wilke, C. O., Wang, J. L., Ofria, C., Lenski, R. E. & Adami, C. Evolution of digital organisms at high mutation rates leads to survival of the flattest. Nature 412, 331–333 (2001)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Sanjuán, R., Cuevas, J. M., Furio, V., Holmes, E. C. & Moya, A. Selection for robustness in mutagenized RNA viruses. PLoS Genet. 3 (6), e93. 939–946 (2007)

    Article  Google Scholar 

  6. 6

    Codoñer, F. M., Daros, J. A., Sole, R. V. & Elena, S. F. The fittest versus the flattest: Experimental confirmation of the quasispecies effect with subviral pathogens. PLoS Pathog. 2 (12), e136. 1187–1193 (2006)

  7. 7

    Maharjan, R. P., Seeto, S. & Ferenci, T. Divergence and redundancy of transport and metabolic rate-yield strategies in a single Escherichia coli population. J. Bacteriol. 189, 2350–2358 (2007)

    CAS  Article  Google Scholar 

  8. 8

    Loeb, L. A. et al. Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc. Natl Acad. Sci. USA 96, 1492–1497 (1999)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Bull, J. J. & Wilke, C. O. Lethal mutagenesis of bacteria. Genetics 180, 1061–1070 (2008)

    Article  Google Scholar 

  10. 10

    Koch, A. L. The pertinence of the periodic selection phenomenon to prokaryote evolution. Genetics 77, 127–142 (1974)

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Levin, B. R. Periodic selection, infectious gene exchange and the genetic structure of E. coli populations. Genetics 99, 1–23 (1981)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Turner, P. E., Souza, V. & Lenski, R. E. Tests of ecological mechanisms promoting the stable coexistence of two bacterial genotypes. Ecology 77, 2119–2129 (1996)

    Article  Google Scholar 

  13. 13

    Pfeiffer, T. & Bonhoeffer, S. Evolution of cross-feeding in microbial populations. Am. Nat. 163, E126–E135 (2004)

    Article  Google Scholar 

  14. 14

    Pfeiffer, T., Schuster, S. & Bonhoeffer, S. Cooperation and competition in the evolution of ATP-producing pathways. Science 292, 504–507 (2001)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Molenaar, D., van Berlo, R., de Ridder, D. & Teusink, B. Shifts in growth strategies reflect tradeoffs in cellular economics. Mol. Syst. Biol. 5 323 10.1038/msb.2009.82 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Doebeli, M. & Ispolatov, I. Complexity and diversity. Science 328, 494–497 (2010)

    ADS  MathSciNet  CAS  Article  Google Scholar 

  17. 17

    Novak, M., Pfeiffer, T., Lenski, R. E., Sauer, U. & Bonhoeffer, S. Experimental tests for an evolutionary trade-off between growth rate and yield in E. coli . Am. Nat. 168, 242–251 (2006)

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Weusthuis, R. A., Pronk, J. T., van den Broek, P. J. & van Dijken, J. P. Chemostat cultivation as a tool for studies on sugar transport in yeasts. Microbiol. Mol. Biol. Rev. 58, 616–630 (1994)

    CAS  Google Scholar 

  19. 19

    Kreft, J. U. Biofilms promote altruism. Microbiology 150, 2751–2760 (2004)

    CAS  Article  Google Scholar 

  20. 20

    Lipson, D. A., Monson, R. K., Schmidt, S. K. & Weintraub, M. N. The trade-off between growth rate and yield in microbial communities and the consequences for under-snow soil respiration in a high elevation coniferous forest. Biogeochemistry 95, 23–35 (2009)

    Article  Google Scholar 

  21. 21

    Marusyk, A. & Polyak, K. Tumor heterogeneity: Causes and consequences. Biochim. Biophys. Acta. Rev. Cancer 1805, 105–117 (2010)

    CAS  Article  Google Scholar 

  22. 22

    Gillies, R. & Gatenby, R. Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J. Bioenerg. Biomembr. 39, 251–257 (2007)

    CAS  Article  Google Scholar 

  23. 23

    Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Krak, N. et al. Blood flow and glucose metabolism in stage IV breast cancer: heterogeneity of response during chemotherapy. Mol. Imaging Biol. 10, 356–363 (2008)

    Article  Google Scholar 

  25. 25

    Bjedov, I. et al. Stress-induced mutagenesis in bacteria. Science 300, 1404–1409 (2003)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Martin, G. & Gandon, S. Lethal mutagenesis and evolutionary epidemiology. Phil. Trans. R. Soc. Lond. B 365, 1953–1963 (2010)

    CAS  Article  Google Scholar 

  27. 27

    Keller, H. B. in Applications of Bifurcation Theory (ed. Rabinowitz, P.) (Academic Press, 1977)

    Google Scholar 

Download references


We thank C. Burch, M. Doebeli and T. Ferenci for discussions. L.D.H. is a Royal Society Wolfson Research Merit Award Holder, R.E.B. holds an EPSRC Leadership Fellowship, and I.G. holds a NERC Advanced Research Fellowship.

Author information




R.E.B. and I.G. wrote the paper, conceived the paper, designed analyses and performed analysis, D.A.L. wrote the paper and performed analysis, L.D.H. wrote the paper, conceived the paper and designed analyses.

Corresponding author

Correspondence to Laurence D. Hurst.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Figures 1-26 with legends and additional references. See Table of Contents on page 1 for full details. (PDF 1496 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Beardmore, R., Gudelj, I., Lipson, D. et al. Metabolic trade-offs and the maintenance of the fittest and the flattest. Nature 472, 342–346 (2011).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links