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.

Robustness against mutations in genetic networks of yeast


There are two principal mechanisms that are responsible for the ability of an organism's physiological and developmental processes to compensate for mutations. In the first, genes have overlapping functions, and loss-of-function mutations in one gene will have little phenotypic effect if there are one or more additional genes with similar functions. The second mechanism has its origin in interactions between genes with unrelated functions, and has been documented in metabolic and regulatory gene networks. Here I analyse, on a genome-wide scale, which of these mechanisms of robustness against mutations is more prevalent. I used functional genomics data from the yeast Saccharomyces cerevisiae to test hypotheses related to the following: if gene duplications are mostly responsible for robustness, then a correlation is expected between the similarity of two duplicated genes and the effect of mutations in one of these genes. My results demonstrate that interactions among unrelated genes are the major cause of robustness against mutations. This type of robustness is probably an evolved response of genetic networks to stabilizing selection.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Sequence similarity versus fitness effect of null mutations in 45 duplicated yeast genes.
Figure 2: Similarity in expression pattern versus fitness effect of null mutations in 45 duplicated yeast genes.
Figure 3: Fitness effect distribution of loss-of-function mutations.
Figure 4: Similar distribution of fitness effects of block-duplicated genes and all other genes on chromosome V.
Figure 5: Genes with weak fitness effect do not have more related genes in the yeast genome than do genes with strong fitness effects.
Figure 6: Genes similar to those with weak fitness effects and to those with strong fitness effects do not show systematic differences in their similarities.


  1. 1

    Wang, Y.K., Schnegelsberg, P.N.J., Dausman, J. & Jaenisch, R. Functional redundancy of the muscle-specific transcription factors myf5 and myogenin. Nature 379, 823– 825 (1996).

    CAS  Article  Google Scholar 

  2. 2

    Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. Mice develop normally without tenascin. Genes Dev. 6, 1821–1831 (1992).

    CAS  Article  Google Scholar 

  3. 3

    Cadigan, K.M., Grossniklaus, U. & Gehring, W.J. Functional redundancy: the respective roles of the 2 sloppy paired genes in Drosophila segmentation. Proc. Natl Acad. Sci. USA 91, 6324–6328 ( 1994).

    CAS  Article  Google Scholar 

  4. 4

    Gonzalez-Gaitan, M., Rothe, M., Wimmer, E.A., Taubert, H. & Jackle, H. Redundant functions of the genes knirps and knirps-related for the establishment of anterior Drosophila head structures. Proc. Natl Acad. Sci. USA 91, 8567– 8571 (1994).

    CAS  Article  Google Scholar 

  5. 5

    Hanks, M., Wurst, W., Ansoncartwright, L., Auerbach, A.B. & Joyner, A.L. Rescue of the en-1 mutant phenotype by replacement of en-1 with en-2. Science 269, 679–682 (1995).

    CAS  Article  Google Scholar 

  6. 6

    Hoffmann, F.M. Drosophila-abl and genetic redundancy in signal transduction. Trends Genet. 7, 351–356 (1991).

    CAS  Article  Google Scholar 

  7. 7

    Dun, R.B. & Fraser, A.S. Selection for an invariant character–lsquo;vibrissa number’–in the house mouse. Nature 181, 1018–1019 (1958).

    CAS  Article  Google Scholar 

  8. 8

    Rendel, J.M. Canalization of the scute phenotype of Drosophila. Evolution 13, 425–439 (1959).

    Article  Google Scholar 

  9. 9

    Rendel, J.M. in Quantitative Genetic Variation (eds Thompson, J.N. & Thoday, J.M.) 139–156 (Academic, New York, 1979).

    Book  Google Scholar 

  10. 10

    Waddington, C.H. The Strategy of the Genes (Macmillan, New York, 1959).

  11. 11

    Rutherford, S.L. & Lindquist, S. Hsp90 buffers development against genetic variation and could link capacity for morphogenic change with environmental stress. Mol. Biol. Cell 9 , 2511–2511 (1998).

    Google Scholar 

  12. 12

    Kacser, H. & Burns, J.A. The molecular basis of dominance. Genetics 97, 639–666 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Smith, V., Chou, K.N., Lashkari, D., Botstein, D. & Brown, P.O. Functional analysis of the genes of yeast chromosome V by genetic footprinting. Science 275, 464–464 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Tautz, D. Redundancies, development and the flow of information. Bioessays 14, 263–266 ( 1992).

    CAS  Article  Google Scholar 

  15. 15

    Fell, D. Understanding the Control of Metabolism (Portland, Miami, 1997).

    Google Scholar 

  16. 16

    Dykhuizen, D.E., Dean, A.M. & Hartl, D.L. Metabolic flux and fitness. Genetics 115, 25–31 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Hartl, D.L., Dykhuizen, D.E. & Dean, A.M. Limits of adaptation: the evolution of selective neutrality. Genetics 111, 655–674 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Dykhuizen, D. & Hartl, D.L. Selective neutrality of 6pgd allozymes in Escherichia coli and the effects of genetic background. Genetics 96, 801–817 ( 1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Edwards, S. & Palsson, B.O. Systems properties of the Haemophilus influenzae rd metabolic genotype. J. Biol. Chem. 274 , 17410–17416 (1999).

    CAS  Article  Google Scholar 

  20. 20

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

    Article  Google Scholar 

  21. 21

    Nadeau, J.H. & Sankoff, D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics 147, 1259–1266 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Seoighe, C. & Wolfe, K.H. Extent of genomic rearrangement after genome duplication in yeast. Proc. Natl Acad. Sci. USA 95, 4447–4452 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Li, X.L. & Noll, M. Evolution of distinct developmental functions of 3 Drosophila genes by acquisition of different cis-regulatory regions. Nature 367, 83– 87 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Chu, S. et al. The transcriptional program of sporulation in budding yeast. Science 282, 699–705 ( 1998).

    CAS  Article  Google Scholar 

  25. 25

    DeRisi, J.L., Iyer, V.R. & Brown, P.O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680– 686 (1997).

    CAS  Article  Google Scholar 

  26. 26

    Spellman, P.T. et al. Comprehensive identification of cell-cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9, 3273–3297 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Wolfe, K.H. & Shields, D.C. Molecular evidence for an ancient duplication of the entire yeast genome. Nature 387, 708–713 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Thatcher, J.W., Shaw, J.M. & Dickinson, W.J. Marginal fitness contributions of nonessential genes in yeast. Proc. Natl Acad. Sci. USA 95, 253–257 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983).

    Book  Google Scholar 

  30. 30

    Seoighe, C. & Wolfe, K.H. Yeast genome evolution in the post-genome era. Curr. Opin. Microbiol. 2, 548– 554 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Winzeler, E.A. et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901–906 (1999).

    CAS  Article  Google Scholar 

  32. 32

    Hubbard, T.J.P., Ailey, B., Brenner, S.E., Murzin, A.G. & Chothia, C. SCOP, structural classification of proteins database: applications to evaluation of the effectiveness of sequence alignment methods and statistics of protein structural data. Acta Crystallogr. D Biol. Crystallogr. 54, 1147–1154 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Doolittle, R.F. Convergent evolution: the need to be explicit. Trends Biochem. Sci. 19, 15–18 ( 1994).

    CAS  Article  Google Scholar 

  34. 34

    Galperin, M.Y., Walker, D.R. & Koonin, E.V. Analogous enzymes: independent inventions in enzyme evolution. Genome Res. 8, 779– 790 (1998).

    CAS  Article  Google Scholar 

  35. 35

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

    Article  Google Scholar 

  36. 36

    Wagner, A. Redundant gene functions and natural selection. J. Evol. Biol. 12, 1–16 (1999 ).

    Article  Google Scholar 

  37. 37

    Wagner, A. The role of pleiotropy, population size fluctuations, and fitness effects of mutations in the evolution of redundant gene functions. Genetics 154, 1389–1401 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Bradshaw, V.A. & McEntee, K. DNA damage activates transcription and transposition of yeast Ty retrotransposons. Mol. Gen. Genet. 218, 465–474 (1989).

    CAS  Article  Google Scholar 

  39. 39

    Paquin, C.E. & Williamson, V.M. Temperature effects on the rate of Ty transposition. Science 226, 53 –55 (1984).

    CAS  Article  Google Scholar 

  40. 40

    Sokal, R.R. & Rohlf, F.J. Biometry (Freeman, New York, 1981).

    Google Scholar 

  41. 41

    Waterman, M.S. General methods of sequence comparison. Bull. Math. Biol. 46, 473–500 (1984).

    CAS  Article  Google Scholar 

  42. 42

    Altschul, S.F. et al. Gapped Blast and Psi-Blast: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    CAS  Article  Google Scholar 

  43. 43

    Dayhoff, M., Schwartz, R.M. & Orcutt, B.C. in Atlas of Protein Sequence and Structure (ed. Dayhoff, M.) 345–352 (National Biomedical Research Foundation, Silver Spring, 1978).

    Google Scholar 

  44. 44

    Pearson, W.R. Searching protein-sequence libraries: comparison of the sensitivity and selectivity of the Smith-Waterman and Fasta algorithms. Genomics 11, 635–650 (1991).

    CAS  Article  Google Scholar 

  45. 45

    Henikoff, S. & Henikoff, J.G. Amino-acid substitution matrices from protein blocks. Proc. Natl Acad. Sci. USA 89, 10915–10919 (1992).

    CAS  Article  Google Scholar 

  46. 46

    Felsenstein, J. PHYLIP (Phylogeny inference package) version 3.2. Cladistics 5, 164–166 (1989).

    Google Scholar 

  47. 47

    Comeron, J.M. A method for estimating the numbers of synonymous and nonsynonymous substitutions per site. J. Mol. Evol. 41, 1152– 1159 (1995).

    CAS  Article  Google Scholar 

  48. 48

    Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 ( 1990).

    CAS  Article  Google Scholar 

Download references


I thank E. Charnov, W. Fontana, P. d'Haeseleer, R. Miller, M. Lynch, D. Natvig and M. Werner-Washburne for discussions on the subject. Th financial and computational support of the Santa Fe Institute and of the Albuquerque High Performance Computing Center is gratefully acknowledged.

Author information



Corresponding author

Correspondence to Andreas Wagner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wagner, A. Robustness against mutations in genetic networks of yeast. Nat Genet 24, 355–361 (2000).

Download citation

Further reading


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