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Sexual reproduction selects for robustness and negative epistasis in artificial gene networks

  • A Corrigendum to this article was published on 05 October 2006


The mutational deterministic hypothesis for the origin and maintenance of sexual reproduction posits that sex enhances the ability of natural selection to purge deleterious mutations after recombination brings them together into single genomes1. This explanation requires negative epistasis, a type of genetic interaction where mutations are more harmful in combination than expected from their separate effects. The conceptual appeal of the mutational deterministic hypothesis has been offset by our inability to identify the mechanistic and evolutionary bases of negative epistasis. Here we show that negative epistasis can evolve as a consequence of sexual reproduction itself. Using an artificial gene network model2,3, we find that recombination between gene networks imposes selection for genetic robustness, and that negative epistasis evolves as a by-product of this selection. Our results suggest that sexual reproduction selects for conditions that favour its own maintenance, a case of evolution forging its own path.

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  1. 1

    Kondrashov, A. S. Deleterious mutations and the evolution of sexual reproduction. Nature 336, 435–440 (1988)

  2. 2

    Siegal, M. L. & Bergman, A. Waddington's canalization revisited: developmental stability and evolution. Proc. Natl Acad. Sci. USA 99, 10528–10532 (2002)

  3. 3

    Wagner, A. Does evolutionary plasticity evolve? Evolution 50, 1008–1023 (1996)

  4. 4

    Lynch, M. et al. Perspective: Spontaneous deleterious mutation. Evolution 53, 645–663 (1999)

  5. 5

    Whitlock, M. C., Phillips, P. C., Moore, F. B. G. & Tonsor, S. J. Multiple fitness peaks and epistasis. Annu. Rev. Ecol. Syst. 26, 601–629 (1995)

  6. 6

    Burch, C. L. & Chao, L. Epistasis and its relationship to canalization in the RNA virus phi 6. Genetics 167, 559–567 (2004)

  7. 7

    de Visser, J. A. G. M., Hoekstra, R. F. & van den Ende, H. An experimental test for synergistic epistasis and its application in Chlamydomonas. Genetics 145, 815–819 (1997)

  8. 8

    Mukai, T. The genetic structure of natural populations of Drosophila melanogaster. VII. Synergistic interaction of spontaneous mutant polygenes controlling viability. Genetics 61, 749–761 (1969)

  9. 9

    Whitlock, M. C. & Bourguet, D. Factors affecting the genetic load in Drosophila: synergistic epistasis and correlations among fitness components. Evolution 54, 1654–1660 (2000)

  10. 10

    Bonhoeffer, S., Chappey, C., Parkin, N. T., Whitcomb, J. M. & Petropoulos, C. J. Evidence for positive epistasis in HIV-1. Science 306, 1547–1550 (2004)

  11. 11

    de Visser, J. A. G. M., Hoekstra, R. F. & van den Ende, H. Test of interaction between genetic markers that affect fitness in Aspergillus niger. Evolution 51, 1499–1505 (1997)

  12. 12

    Elena, S. F. & Lenski, R. E. Test of synergistic interactions among deleterious mutations in bacteria. Nature 390, 395–398 (1997)

  13. 13

    Michalakis, Y. & Roze, D. Evolution. Epistasis in RNA viruses. Science 306, 1492–1493 (2004)

  14. 14

    Wilke, C. O. & Adami, C. Interaction between directional epistasis and average mutational effects. Proc. R. Soc. Lond. B 268, 1469–1474 (2001)

  15. 15

    You, L. & Yin, J. Dependence of epistasis on environment and mutation severity as revealed by in silico mutagenesis of phage T7. Genetics 160, 1273–1281 (2002)

  16. 16

    Kawecki, T. J. The evolution of genetic canalization under fluctuating selection. Evolution 54, 1–12 (2000)

  17. 17

    Rice, S. H. The evolution of canalization and the breaking of von Baer's laws: Modeling the evolution of development with epistasis. Evolution 52, 647–656 (1998)

  18. 18

    Wagner, G. P., Booth, G. & Bagheri-Chaichian, H. A population genetic theory of canalization. Evolution 51, 329–347 (1997)

  19. 19

    Nijhout, H. F. The nature of robustness in development. Bioessays 24, 553–563 (2002)

  20. 20

    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)

  21. 21

    de Visser, J. A. G. M. et al. Perspective: Evolution and detection of genetic robustness. Evolution 57, 1959–1972 (2003)

  22. 22

    Stearns, S. C. The evolutionary links between fixed and variable traits. Acta Paleontol. Pol. 38, 215–232 (1994)

  23. 23

    Stelling, J., Sauer, U., Szallasi, Z., Doyle, F. J. III & Doyle, J. Robustness of cellular functions. Cell 118, 675–685 (2004)

  24. 24

    Charlesworth, B. & Barton, N. Recombination load associated with selection for increased recombination. Genet. Res. 67, 27–41 (1996)

  25. 25

    Wagner, G. P., Laubichler, M. D. & Bagheri-Chaichian, H. Genetic measurement of theory of epistatic effects. Genetica 102–103, 569–580 (1998)

  26. 26

    Milo, R. et al. Network motifs: Simple building blocks of complex networks. Science 298, 824–827 (2002)

  27. 27

    Barton, N. H. & Keightley, P. D. Understanding quantitative genetic variation. Nature Rev. Genet. 3, 11–21 (2002)

  28. 28

    Maynard Smith, J. The Evolution of Sex (Cambridge Univ. Press, Cambridge, 1978)

  29. 29

    Crawley, M. J. Statistical Computing (Wiley, Chichester, 2002)

  30. 30

    Jaeger, J. et al. Dynamical analysis of regulatory interactions in the gap gene system of Drosophila melanogaster. Genetics 167, 1721–1737 (2004)

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We thank T. Flatt, Y. Fofanov, F. Galis, J. Kingsolver, A. Monteiro, M. Travisano and G. Wagner for discussions. The UH, UNC and NIH (grant to C.L.B.) provided financial support.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Correspondence to Ricardo B. R. Azevedo.

Supplementary information

Supplementary Notes

This file was replaced on 5 October 2006. See Corrigendum to original paper. (PDF 284 kb)

This file contains Supplementary Methods, Supplementary Figures and their legends, and respective additional references. The Supplementary Methods contain a list of default network and population genetic parameters, methods for the experiments described in Fig. 3b (main text), details of the software used, and methods for the experiments reported in the Supplementary Figures. The Supplementary Figures show sensitivity analyses of the evolutionary responses in robustness and directional epistasis to changes in various network and population genetic parameters (Supplementary Figures 1, 4–9), estimates of the initial recombination load in the experiments described in Fig. 3b (main text) (Supplementary Figure 2), and the correlation between genetic robustness and directional epistasis in random networks (Supplementary Figure 3).

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Further reading

Figure 1: Types of directional epistasis for deleterious mutations.
Figure 2: Application of our network model to the gap gene system of Drosophila melanogaster.
Figure 3: Sexual reproduction selects for mutational robustness and negative epistasis.


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