Skip to main content

Thank you for visiting nature.com. 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.

  • Review Article
  • Published:

Evolving responsively: adaptive mutation

Nature Reviews Genetics volume 2, pages 504–515 (2001)Cite this article

Key Points

  • 'Adaptive' mutation denotes a collection of stress responses that include the induction of spontaneous mutation mechanisms in slowly growing or non-growing cells. In adaptive mutation, some of the mutations generated enable these cells to grow.

  • It was suggested initially that mutations were directed specifically to genes under selection; however, this idea has not been supported in the few examples studied.

  • The adaptive reversion of an episomal lac frameshift allele in Escherichia coli involves both gene (point) mutations that revert the frameshift and amplifications of the weakly functional lac allele.

  • The mechanisms of adaptive mutation in the lac system differ from spontaneous mutation in growing cells in that the former involve DNA recombination and repair proteins, the SOS response to DNA damage (cell-cycle checkpoint control), the special error-prone DNA polymerase pol IV (or DinB) and transient limitation of mismatch repair function.

  • The F′ conjugative plasmid contributes to adaptive mutation, but recombination-protein-dependent mutation also occurs in the bacterial chromosome.

  • In the lac system, some or all adaptive mutants arise from a small subpopulation of cells in which hypermutation at other sites has occurred. There are hot and cold spots for this genome-wide mutation.

  • Other bacterial and yeast systems show additional types of stationary- phase and adaptive mutation mechanisms. These include transposon-mediated mutation and transcription-associated mutation.

  • Mutation using similar mechanisms might occur in somatic hypermutation of immunoglobulin genes, in mutations associated with double-stranded-break repair in yeast and in phase variation of microbial pathogens.

Abstract

A basic principle of genetics is that the likelihood that a particular mutation occurs is independent of its phenotypic consequences. The concept of adaptive mutation seemed to challenge this principle with the discoveries of mutations stimulated by stress, some of which allow adaptation to the stress. The emerging mechanisms of adaptive genetic change cast evolution, development and heredity into a new perspective, indicating new models for the genetic changes that fuel these processes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Adaptive point mutation and amplification in the lac frameshift system.
Figure 2: Two models for generating adaptive point mutations through recombination proteins.
Figure 3: Models for adaptive point mutation and amplification.
Figure 4: Hypothesis: hot and cold spots in the Escherichia coli chromosome are dictated by proximity to double-stranded breaks.

Similar content being viewed by others

References

  1. Adams, D. The Hitch-hiker's Guide to the Galaxy: The Original Radio Scripts (Pan Books, Ltd, London, 1985).

    Google Scholar 

  2. Mayr, E. The Growth of Biological Thought, Diversity, Evolution, and Inheritance (Belknap, Cambridge, Massachusetts, 1982).

    Google Scholar 

  3. Luria, S. E. & Delbrück, M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28, 491–511 (1943).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Newcombe, H. B. Origin of bacterial variants. Nature 164, 150–151 (1949).

    CAS  PubMed  Google Scholar 

  5. Lederberg, J. & Lederberg, E. M. Replica plating and indirect selection of bacterial mutants. J. Bacteriol. 63, 399–406 (1952).References 3–5 are classic papers that provided the first evidence that mutations can occur independently of specific interaction with an environment in which the mutation is selected. They did not look for mutations induced by contact with a selective environment.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shapiro, J. A. Observations on the formation of clones containing araB–lacZ fusions. Mol. Gen. Genet. 194, 79–90 (1984).

    CAS  PubMed  Google Scholar 

  7. Cairns, J., Overbaugh, J. & Miller, S. The origin of mutants. Nature 335, 142–145 (1988).References 6 and 7 inaugurated the modern study of adaptive mutation in bacteria. However, reference 11 showed that most putative adaptive mutations in reference 7 were really growth dependent.

    CAS  PubMed  Google Scholar 

  8. Novick, A. & Szilard, L. Experiments on spontaneous and chemically induced mutations of bacteria growing in the chemostat. Cold Spring Harbor Symp. Quant. Biol. 16, 337–343 (1951).

    CAS  PubMed  Google Scholar 

  9. Ryan, F. J. Distribution of numbers of mutant bacteria in replicate cultures. Nature 169, 882–883 (1952).

    Google Scholar 

  10. Ryan, F. Spontaneous mutations in non-dividing bacteria. Genetics 40, 726–738 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Prival, M. J. & Cebula, T. A. Adaptive mutation and slow-growing revertants of an Escherichia coli lacZ amber mutant. Genetics 144, 1337–1341 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cairns, J. & Foster, P. L. Adaptive reversion of a frameshift mutation in Escherichia coli. Genetics 128, 695–701 (1991).Description of the lac frameshift reversion assay for adaptive mutation and demonstration of a role for the SOS response, also explored in reference 67.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hastings, P. J., Bull, H. J., Klump, J. R. & Rosenberg, S. M. Adaptive amplification: an inducible chromosomal instability mechanism. Cell 103, 723–731 (2000).Shows that amplification can be an adaptive response. It also disproves predictions of a model (reference 49 ) in which amplification is postulated to lead to late Lac reversions through a growth-dependent mutation process.

    CAS  PubMed  Google Scholar 

  14. Hall, B. G. Adaptive evolution that requires multiple spontaneous mutations. I. Mutations involving an insertion sequence. Genetics 120, 887–897 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hall, B. G. Spontaneous point mutations that occur more often when advantageous than when neutral. Genetics 126, 5–16 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Boe, L. & Marinus, M. G. Role of plasmid multimers in mutation to tetracycline resistance. Mol. Microbiol. 5, 2541–2545 (1991).

    CAS  PubMed  Google Scholar 

  17. Prival, M. J. & Cebula, T. A. Sequence analysis of mutations arising during prolonged starvation of Salmonella typhimurium. Genetics 132, 303–310 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jayaraman, R. Cairnsian mutagenesis in Escherichia coli: genetic evidence for two pathways regulated by mutS and mutL genes. J. Genet. 71, 23–41 (1992).

    Google Scholar 

  19. Bridges, B. Spontaneous mutation in stationary-phase Escherichia coli WP2 carrying various DNA repair alleles. Mutat. Res. 302, 173–176 (1993).

    CAS  PubMed  Google Scholar 

  20. Maenhaut-Michel, G., Blake, C. E., Leach, D. R. & Shapiro, J. A. Different structures of selected and unselected araB–lacZ fusions. Mol. Microbiol. 23, 133–145 (1997).

    Google Scholar 

  21. Galitski, T. & Roth, J. R. A search for a general phenomenon of adaptive mutability. Genetics 143, 645–659 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kasak, L., Horak, R. & Kivisaar, M. Promoter-creating mutations in Pseudomonas putida: a model system for the study of mutation in starving bacteria. Proc. Natl Acad. Sci. USA 94, 3134–3139 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Hall, B. G. Adaptive mutagenesis at ebgR is regulated by PhoPQ. J. Bacteriol. 180, 2862–2865 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Massey, R. C., Rainey, P. B., Sheehan, B. J., Keane, O. M. & Dorman, C. J. Environmentally constrained mutation and adaptive evolution in Salmonella. Curr. Biol. 9, 1477–1480 (1999).References 14–24 report stationary-phase mutations, many of which do not form by mechanisms similar to the lac system. Included are several that have not been distinguished mechanistically from growth-dependent mutation. Reference 25 describes transcription-associated mutation in bacteria.

    CAS  PubMed  Google Scholar 

  25. Wright, B. E., Longacre, A. & Reimers, J. M. Hypermutation in derepressed operons of Escherichia coli K12. Proc. Natl Acad. Sci. USA 96, 5089–5094 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Steele, D. F. & Jinks-Robertson, S. An examination of adaptive reversion in Saccharomyces cerevisiae. Genetics 132, 9–21 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Greene, C. N. & Jinks-Robertson, S. Comparison of spontaneous and adaptive mutation spectra in yeast. J. Genet. 78, 51–55 (1999).

    CAS  Google Scholar 

  28. Hall, B. G. Selection-induced mutations occur in yeast. Proc. Natl Acad. Sci. USA 89, 4300–4303 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Baranowska, H., Policinska, Z. & Jachymczyk, W. J. Effects of the CDC2 gene on adaptive mutation in the yeast Saccharomyces cerevisiae. Curr. Genet. 28, 521–525 (1995).

    CAS  PubMed  Google Scholar 

  30. Heidenreich, E. & Wintersberger, U. Starvation for a specific amino acid induces high frequencies of rho− mutants in Saccharomyces cerevisiae. Curr. Genet. 31, 408–413 (1997).

    CAS  PubMed  Google Scholar 

  31. Heidenreich, E. & Wintersberger, U. Replication-dependent and selection-induced mutations in respiration-competent and respiration-deficient strains of Saccharomyces cerevisiae. Mol. Gen. Genet. 260, 395–400 (1998).

    CAS  PubMed  Google Scholar 

  32. Heidenreich, E. & Wintersberger, U. Adaptive reversion of a frameshift mutation in arrested Saccharomyces cerevisiae cells by simple deletions in mononucleotide repeats. Mutat. Res. 473, 101–107 (2001).The seven papers above report on adaptive mutations in yeast.

    CAS  PubMed  Google Scholar 

  33. Taddei, F., Halliday, J. A., Matic, I. & Radman, M. Genetic analysis of mutagenesis in aging Escherichia coli colonies. Mol. Gen. Genet. 256, 277–281 (1997).In this paper, RecA- and RecB-dependent stationary-phase mutations are described that might be similar to recombination-dependent stationary-phase point mutation in the lac system. These occur in cells with or without a conjugative plasmid. There are some differences in genetic requirements between these and the lac system mutations.

    CAS  PubMed  Google Scholar 

  34. Lamrani, S. et al. Starvation-induced Mucts62-mediated coding sequence fusion: a role for ClpXP, Lon, RpoS and Crp. Mol. Microbiol. 32, 327–343 (1999).

    CAS  PubMed  Google Scholar 

  35. Friedberg, E. C., Feaver, W. J. & Gerlach, V. L. The many faces of DNA polymerases: strategies for mutagenesis and for mutational avoidance. Proc. Natl Acad. Sci. USA 97, 5681–5683 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. McKenzie, G. J., Lombardo, M.-J. & Rosenberg, S. M. Recombination-dependent mutation in Escherichia coli occurs in stationary phase. Genetics 149, 1563–1565 (1998).

    Google Scholar 

  37. Rosenberg, S. M., Longerich, S., Gee, P. & Harris, R. S. Adaptive mutation by deletions in small mononucleotide repeats. Science 265, 405–407 (1994).

    CAS  PubMed  Google Scholar 

  38. Foster, P. L. & Trimarchi, J. M. Adaptive reversion of a frameshift mutation in Escherichia coli by simple base deletions in homopolymeric runs. Science 265, 407–409 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Harris, R. S., Longerich, S. & Rosenberg, S. M. Recombination in adaptive mutation. Science 264, 258–260 (1994).

    CAS  PubMed  Google Scholar 

  40. Foster, P. L., Trimarchi, J. M. & Maurer, R. A. Two enzymes, both of which process recombination intermediates, have opposite effects on adaptive mutation in Escherichia coli. Genetics 142, 25–37 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Harris, R. S., Ross, K. J. & Rosenberg, S. M. Opposing roles of the Holliday junction processing systems of Escherichia coli in recombination-dependent adaptive mutation. Genetics 142, 681–691 (1996).References 37 and 38 show that the sequences of Lac adaptive mutations differ from growth-dependent Lac reversions. The former show simple-repeat instability, which is characteristic of template slippage polymerase errors. References 39–41 show the specific requirement for recombination and double-stranded break-repair proteins for stationary-phase Lac reversion.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kowalczykowski, S. C. Initiation of genetic recombination and recombination-dependent replication. Trends Biochem. Sci. 25, 156–165 (2000).

    CAS  PubMed  Google Scholar 

  43. Mosig, G. The essential role of recombination in phage T4 growth. Annu. Rev. Genet. 21, 347–371 (1987).

    CAS  PubMed  Google Scholar 

  44. Skalka, A. in Mechanisms in Recombination (ed. Grell, R. R.) 421–432 (Plenum, New York, 1974).

    Google Scholar 

  45. Kogoma, T. Stable DNA replication: interplay between DNA replication, homologous recombination, and transcription. Microbiol. Mol. Biol. Rev. 61, 212–238 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Radding, C. M. (ed.) National Academy of Sciences Colloquium: Links Between Recombination and Replication (Proc. Natl Acad. Sci. USA, 2001, in the press).

    Google Scholar 

  47. Kuzminov, A. Collapse and repair of replication forks in Escherichia coli. Mol. Microbiol. 16, 373–384 (1995).

    CAS  PubMed  Google Scholar 

  48. Rosenberg, S. M., Harris, R. S., Longerich, S. & Galloway, A. M. Recombination-dependent mutation in non-dividing cells. Mutat. Res. 350, 69–76 (1996).

    PubMed  Google Scholar 

  49. Andersson, D. I., Slechta, E. S. & Roth, J. R. Evidence that gene amplification underlies adaptive mutability of the bacterial lac operon. Science 282, 1133–1135 (1998).

    CAS  PubMed  Google Scholar 

  50. Motamedi, M., Szigety, S. K. & Rosenberg, S. M. Double-strand-break repair in Escherichia coli: physical evidence for a DNA replication mechanism in vivo. Genes Dev. 13, 2889–2903 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Holbeck, S. L. & Strathern, J. N. A role for REV3 in mutagenesis during double-strand break repair in Saccharomyces cerevisiae. Genetics 147, 1017–1024 (1997).DSB-repair-promoted mutation in yeast, requiring DinB/UmuDC/Rad30/Rev1 DNA polymerase superfamily member, Rev3.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ripley, L. S. Frameshift mutation: determinants of specificity. Annu. Rev. Genet. 24, 189–213 (1990).

    CAS  PubMed  Google Scholar 

  53. Foster, P. L., Gudmundsson, G., Trimarchi, J. M., Cai, H. & Goodman, M. F. Proofreading-defective DNA polymerase II increases adaptive mutation in Escherichia coli. Proc. Natl Acad. Sci. USA 92, 7951–7955 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Harris, R. S., Bull, H. J. & Rosenberg, S. M. A direct role for DNA polymerase III in adaptive reversion of a frameshift mutation in Escherichia coli. Mutat. Res. 375, 19–24 (1997).

    CAS  PubMed  Google Scholar 

  55. Modrich, P. & Lahue, R. Mismatch repair in replication fidelity, genetic recombination, and cancer. Annu. Rev. Biochem. 65, 101–133 (1996).

    CAS  PubMed  Google Scholar 

  56. Fishel, R. Signaling mismatch repair in cancer. Nature Med. 5, 1239–1241 (1999).

    CAS  PubMed  Google Scholar 

  57. Longerich, S., Galloway, A. M., Harris, R. S., Wong, C. & Rosenberg, S. M. Adaptive mutation sequences reproduced by mismatch repair deficiency. Proc. Natl Acad. Sci. USA 92, 12017–12020 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Torkelson, J. et al. Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation. EMBO J. 16, 3303–3311 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Rosche, W. A. & Foster, P. L. The role of transient hypermutators in adaptive mutation in Escherichia coli. Proc. Natl Acad. Sci. USA 96, 6862–6867 (1999).References 58 and 59 , and also reference 77 , provide evidence that Lac+ adaptive mutants of Escherichia coli carry high frequencies of unselected mutations, which are not carried by starved cells that remained Lac−. This indicates that some or all Lac+ adaptive mutants originate in a globally hypermutable cell subpopulation. The data of reference 58 show hot and cold sites for this hypermutation.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Harris, R. S. et al. Mismatch repair protein MutL becomes limiting during stationary-phase mutation. Genes Dev. 11, 2426–2437 (1997).Evidence that cells undergoing adaptive mutation in the lac system have transient mismatch repair deficiency that can be alleviated by overproduction of MutL protein. See also reference 57 . The interpretation of the data is criticized in reference 61 , and this criticism is rebutted in reference 62.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Foster, P. L. Are adaptive mutations due to a decline in mismatch repair? The evidence is lacking. Mutat. Res. 436, 179–184 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Harris, R. S. et al. Mismatch repair is diminished during stationary-phase mutation. Mutat. Res. 437, 51–60 (1999).

    CAS  PubMed  Google Scholar 

  63. Zhao, J. & Winkler, M. E. Reduction of GC→TA transversion mutation by overexpression of MutS in Escherichia coli K-12. J. Bacteriol. 182, 5025–5028 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Brègeon, D., Matic, I., Radman, M. & Taddei, F. Mismatch repair: genetic defects and down regulation. J. Genet. 78, 21–28 (1999).

    Google Scholar 

  65. McKenzie, G. J., Lee, P. L., Lombardo, M.-J., Hastings, P. J. & Rosenberg, S. M. SOS mutator DNA polymerase IV functions in adaptive mutation and not adaptive amplification. Mol. Cell 7, 571–579 (2001).Shows that pol IV or DinB, of the DinB/UmuDC DNA polymerase superfamily, is required specifically for most stationary-phase mutation at lac.

    CAS  PubMed  Google Scholar 

  66. Sutton, M. D., Smith, B. T., Godoy, V. G. & Walker, G. C. The SOS response: recent insights into UmuDC-dependent mutagenesis and DNA damage tolerance. Annu. Rev. Genet. 34, 479–497 (2000).

    CAS  PubMed  Google Scholar 

  67. McKenzie, G. J., Harris, R. S., Lee, P. L. & Rosenberg, S. M. The SOS response regulates adaptive mutation. Proc. Natl Acad. Sci. USA 97, 6646–6651 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Strauss, B. S., Roberts, R., Francis, L. & Pouryazdanparast, P. Role of the dinB gene product in spontaneous mutation in Escherichia coli with an impaired replicative polymerase. J. Bacteriol. 182, 6742–6750 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Napolitano, R., Janel-Bintz, R., Wagner, J. & Fuchs, R. P. P. All three SOS-inducible DNA polymerases (pol II, pol IV, and pol V) are involved in induced mutagenesis. EMBO J. 19, 6259–6265 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wagner, J. et al. The dinB gene encodes a novel E. coli DNA polymerase, DNA pol IV, involved in mutagenesis. Mol. Cell 4, 281–286 (1999).

    CAS  PubMed  Google Scholar 

  71. Kim, S.-Y. et al. Multiple pathways for SOS-induced mutagenesis in Escherichia coli: an SOS gene product (DinB/P) enhances frameshift mutations in the absence of any exogenous agents that damage DNA. Proc. Natl Acad. Sci. USA 94, 13792–13797 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wagner, J. & Nohmi, T. Escherichia coli DNA polymerase IV mutator activity: genetic requirements and mutational specificity. J. Bacteriol. 182, 4587–4595 (2000).Reference 70 shows that DinB is an error-prone polymerase. References 71 and 72 show that DinB protein causes mutations simply by being overproduced in cells, without obvious DNA damage.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Radman, M. SOS repair hypothesis: phenomenology of an inducible DNA repair which is accompanied by mutagenesis. Basic Life Sci. 5A, 355–367 (1975).

    CAS  PubMed  Google Scholar 

  74. Echols, H. SOS functions, cancer and inducible evolution. Cell 25, 1–2 (1981).

    CAS  PubMed  Google Scholar 

  75. Schaaper, R. M. & Radman, M. The extreme mutator effect of Escherichia coli mutD5 results from saturation of mismatch repair by excessive DNA replication errors. EMBO J. 8, 3511–3516 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Foster, P. L. Nonadaptive mutations occur in the F′ episome during adaptive mutation conditions in Escherichia coli. J. Bacteriol. 179, 1550–1554 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Godoy, V. G., Gizatullin, F. S. & Fox, M. S. Some features of the mutability of bacteria during nonlethal selection. Genetics 154, 49–59 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rosenberg, S. M., Thulin, C. & Harris, R. S. Transient and heritable mutators in adaptive evolution in the lab and in nature. Genetics 148, 1559–1566 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bull, H. J., McKenzie, G. J., Hastings, P. J. & Rosenberg, S. M. Evidence that stationary-phase hypermutation in the E. coli chromosome is promoted by recombination. Genetics 154, 1427–1437 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bull, H. J., McKenzie, G. J., Hastings, P. J. & Rosenberg, S. M. The contribution of transiently hypermutable cells to mutation in stationary phase. Genetics 156, 925–926 (2000).

    Google Scholar 

  81. Bull, H. J., Lombardo, M.-J. & Rosenberg, S. M. Stationary-phase mutation in the bacterial chromosome: recombination protein and DNA polymerase IV dependence. Proc. Natl Acad. Sci. USA (2001, in the press).The first demonstration of recombination-protein (RecA and RuvC)-dependent and DNA-pol IV-dependent mutation in the Escherichia coli chromosome, in stationary phase. This shows that Rec- and pol IV-dependent stationary-phase mutation can affect the main bacterial genome, as well as plasmid-borne genes.

  82. Cairns, J. The contribution of transiently hypermutable cells to mutation in stationary phase. Genetics 156, 923–926 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Rosenberg, S. M. Mutation for survival. Curr. Opin. Genet. Dev. 7, 829–834 (1997).

    CAS  PubMed  Google Scholar 

  84. Foster, P. L. & Trimarchi, J. M. Adaptive reversion of an episomal frameshift mutation in Escherichia coli requires conjugal functions but not actual conjugation. Proc. Natl Acad. Sci. USA 92, 5487–5490 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Radicella, J. P., Park, P. U. & Fox, M. S. Adaptive mutation in Escherichia coli: a role for conjugation. Science 268, 418–420 (1995).

    CAS  PubMed  Google Scholar 

  86. Galitski, T. & Roth, J. R. Evidence that F′ transfer replication underlies apparent adaptive mutation. Science 268, 421–423 (1995).

    CAS  PubMed  Google Scholar 

  87. Foster, P. L. & Trimarchi, J. M. Conjugation is not required for adaptive reversion of an episomal frameshift mutation in Escherichia coli. J. Bacteriol. 177, 6670–6671 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Rosenberg, S. M., Harris, R. S. & Torkelson, J. Molecular handles on adaptive mutation. Mol. Microbiol. 18, 185–189 (1995).

    CAS  PubMed  Google Scholar 

  89. Lombardo, M.-J., Torkelson, J., Bull, H. J., McKenzie, G. J. & Rosenberg, S. M. Mechanisms of genome-wide hypermutation in stationary phase. Ann. NY Acad. Sci. 870, 275–289 (1999).

    CAS  PubMed  Google Scholar 

  90. Yarmolinsky, M. B. Programmed cell death in bacterial populations. Science 267, 836–837 (1995).

    CAS  PubMed  Google Scholar 

  91. Firth, N., Ippen-Ihler, K. & Skurray, R. H. in Escherichia coli and Salmonella: Cellular and Molecular Biology (eds Neidhardt, F. C. et al.) 2377–2401 (ASM, Washington, DC, 1996).

    Google Scholar 

  92. Whoriskey, S. K., Nghiem, V.-H., Leong, P.-M., Masson, J.-M. & Miller, J. H. Genetic rearrangement and gene amplification in Escherichia coli: DNA sequences at the junctures of amplified gene fusions. Genes Dev. 1, 227–237 (1987).

    CAS  PubMed  Google Scholar 

  93. Tlsty, T. D., Margolin, B. H. & Lum, K. Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbrück fluctuation analysis. Proc. Natl Acad. Sci. USA 86, 9441–9445 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Pipiras, E., Coquelle, A., Bieth, A. & Debatisse, M. Interstitial deletions and intrachromosomal amplification initiated from a double-strand break targeted to a mammalian chromosome. EMBO J. 17, 325–333 (1998).Demonstration that DNA double-stranded breaks provoke amplification in mammalian cells (as it is implied that they do in Escherichia coli , reference 13).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ono, S. Evolution by Gene Duplication (Springer, Berlin and New York, 1970).

    Google Scholar 

  96. Jasin, M. in DNA Damage and Repair. 3. Advances from Phage to Humans (eds Nickoloff, J. A. & Hoekstra, M. F.) 207–235 (Humana, Inc., Totowa, New Jersey, 1998).

    Google Scholar 

  97. Brodeur, G. M. & Hogarty, M. D. in The Genetic Basis of Human Cancer (eds Vogelstein, B. & Kinzler, K. W.) 161–172 (McGraw–Hill, New York, 1998).

    Google Scholar 

  98. Coquelle, A., Pipiras, E., Toledo, F., Buttin, G. & Debatisse, M. Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell 89, 215–225 (1997).

    CAS  PubMed  Google Scholar 

  99. Deitsch, K. W., Moxon, E. R. & Wellems, T. E. Shared themes of antigenic variation and virulence in bacterial, protozoal, and fungal infections. Microbiol. Mol. Biol. Rev. 61, 281–293 (1997).Review of the importance of simple repeat tracts and frameshift mutation in the expression of genes used in pathogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Saunders, N. J. et al. Repeat-associated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58. Mol. Microbiol. 37, 207–215 (2000).

    CAS  PubMed  Google Scholar 

  101. Martinez, J. L. & Baquero, F. Mutation frequencies and antibiotic resistance. Antimicrob. Agents Chemother. 44, 1771–1777 (2000).An excellent review of mutation-based routes to antibiotic resistance, in which it is pointed out that even antibiotics that kill cells can be non-lethal, and thus capable of stimulating stress-promoted mutations at lower concentrations.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zambrano, M. M. & Kolter, R. GASPing for life in stationary phase. Cell 86, 181–184 (1996).

    CAS  PubMed  Google Scholar 

  103. LeClerc, J. E., Li, B., Payne, W. L. & Cebula, T. A. High mutation frequencies among Escherichia coli and Salmonella pathogens. Science 274, 1208–1211 (1996).

    CAS  PubMed  Google Scholar 

  104. Denamur, E. et al. Evolutionary implications of the frequent horizontal transfer of mismatch repair genes. Cell 103, 711–721 (2000).

    CAS  PubMed  Google Scholar 

  105. Cashel, M., Gentry, D. R., Hernandez, V. J. & Vinella, D. in Escherichia coli and Salmonella: Cellular and Molecular Biology (eds Neidhardt, F. C. et al.) 1458–1496 (ASM, Washington, DC, 1996).

    Google Scholar 

  106. Datta, A. & Jinks-Robertson, S. Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 268, 1616–1619 (1995).

    CAS  PubMed  Google Scholar 

  107. Davis, B. D. Transcriptional bias: a non-Lamarckian mechanism for substrate-induced mutations. Proc. Natl Acad. Sci. USA 86, 5005–5009 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Strauss, B. S. The origin of point mutations in human tumor cells. Cancer Res. 52, 249–253 (1992).One of the first suggestions that adaptive mutation mechanisms are apt models for mutations that lead to cancer. See also references 37, 110 and 111.

    CAS  PubMed  Google Scholar 

  109. Hall, B. G. Adaptive mutations in Escherichia coli as a model for the multiple mutational origins of cancer. Proc. Natl Acad. Sci. USA 92, 5669–5673 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Finch, C. E. & Goodman, M. F. Relevance of 'adaptive' mutations arising in non-dividing cells of microorganisms to age-related changes in mutant phenotypes of neurons. Trends Neurosci. 20, 501–507 (1997).

    CAS  PubMed  Google Scholar 

  111. Drake, J. W. Spontaneous mutation. Annu. Rev. Genet. 25, 125–146 (1991).

    CAS  PubMed  Google Scholar 

  112. Walter, C. A., Intano, G. W., McCarrey, J. R., McMahan, C. A. & Walter, R. B. Mutation frequency declines in spermatogenesis in young mice but increases in old mice. Proc. Natl Acad. Sci. USA 95, 10015–10019 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Swanson, W. J., Yang, Z., Wolfner, M. F. & Aquadro, C. F. Positive Darwinian selection drives the evolution of several female reproductive proteins in mammals. Proc. Natl Acad. Sci. USA 98, 2509–2514 (2001).The discovery of hypervariable genes that encode the coat proteins of mammalian eggs. Perhaps this, and the cognate hypervariable genes that encode sperm surface proteins, are targets for mammalian DinB1, a mutator DNA polymerase expressed in the germ line.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Harris, R. S., Kong, Q. & Maizels, N. Somatic hypermutation and the three R's: repair, replication and recombination. Mutat. Res. 436, 157–178 (1999).

    CAS  PubMed  Google Scholar 

  115. Jacobs, H., Rajewsky, K., Fukita, Y. & Bross, L. Indirect and direct evidence for DNA double-strand breaks in hypermutating immunoglobulin genes. Phil. Trans. R. Soc. Lond. B 356, 119–125 (2001).

    CAS  Google Scholar 

  116. McDonald, J. P. et al. DNA polymerase iota and related Rad30-like enzymes. Phil. Trans. R. Soc. Lond. B356, 53–60 (2001).

    CAS  Google Scholar 

  117. True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).

    CAS  PubMed  Google Scholar 

  118. Delbrück, M. Cold Spring Harbor Symp. Quant. Biol. 11, 154 (1946).

    Google Scholar 

  119. Stewart, F. M., Gordon, D. M. & Levin, B. R. Fluctuation analysis: the probability distribution of the number of mutants under different conditions. Genetics 124 (1990).

  120. Higgins, N. P., Kato, K. & Strauss, B. J. A model for replication repair in mammalian cells Mol. Biol. 101, 417–425 (1976).

    CAS  Google Scholar 

  121. Louarn, J.-M., Louarn, J., Francois, V. & Patte, J. Analysis and possible role of hyperrecombination in the terminus region of the Escherichia coli chromosome. J. Bacteriol. 173, 5096–5104 (1991).

    Google Scholar 

  122. Seigneur, M., Bidnenko, V., Ehrlich, S. D. & Michel, B. RuvAB acts at arrested replication forks. Cell 95, 419–430 (1998).

    CAS  PubMed  Google Scholar 

  123. Powell, S. C. & Wartell, R. M. Different characteristics distinguish early versus late arising adaptive mutations in Escherichia coli FC40. Mutat. Res. 473, 219–228 (2001).

    CAS  PubMed  Google Scholar 

  124. Akerlund, T., Nordstrom, K. & Bernander, R. Analysis of cell size and DNA content in exponentially growing and stationary-phase batch cultures of Escherichia coli. J. Bacteriol. 177, 6791–6797 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Anderson, R. P. & Roth, J. R. Spontaneous tandem duplications in Salmonella typhimurium arise by unequal recombination between rRNA (rrn) cistrons. Proc. Natl Acad. Sci. USA 78, 3113–3117 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Zan, H. et al. The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. Immunity 14, 643–653 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Rogozin, I. B., Pavlov, Y. I., Bebenek, K., Matsuda, T. & Kunkel, T. A. Somatic mutation hotspots correlate with DNA polymerase eta error spectrum. Nature Immunol. 2, 530–536 (2001).

    CAS  Google Scholar 

  128. Zeng, X. et al. DNA polymerase eta is an A–T mutator in somatic hypermutation of immunoglobulin variable genes. Nature Immunol. 2, 537–541 (2001).

    CAS  Google Scholar 

  129. Chicurel, M. Can organisms speed their own evolution? Science 292, 1824–1827 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I apologize to my many colleagues whose relevant papers I could not cite owing to space limitations. Thanks to P. J. Hastings, S. Jinks-Robertson, M.-J. Lombardo, N. Maizels and B. Wright for discussions; C. Dorman and J. Strathern for communicating unpublished results; and W. Arber, J. Drake, E. Friedberg, P. J. Hastings, M.-J. Lombardo, G. J. McKenzie, J. Ninio, J. Petrosino and E. Witkin for comments on the manuscript. Supported by grants from the National Institutes of Health (USA).

Author information

Authors and Affiliations

  1. Departments of Molecular and Human Genetics, Biochemistry, and Molecular Virology and Microbiology, Baylor College of Medicine, Room S809A, Mail Stop 225, 1 Baylor Plaza, Houston, 77030-3411, Texas, USA

    Susan M. Rosenberg

Authors
  1. Susan M. Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

FURTHER INFORMATION

Fluctuation test of Luria and Delbrück

ENCYCLOPEDIA OF LIFE SCIENCES

Recombinational DNA repair in bacteria: postreplication

Eukaryotic recombination: initiation by double-strand breaks

SOS response

Topoisomerases

Glossary

AMBER MUTATION

A mutation due to the introduction of a stop codon (UAG) in the coding sequence of a gene that results in premature termination of translation.

POINT MUTATIONS

Small changes to DNA, such as base substitutions, small deletion and insertion (frameshift) mutations, made in the context of a gene. They are contrasted here with large-scale genome rearrangements such as gene amplifications and large deletions, inversions, translocations and chromosomal instability.

F′ CONJUGATIVE PLASMID

The F plasmid is a 100-kb extrachromosomal DNA replicon in bacteria that is transmissible between bacteria through conjugation (a specialized sexual process requiring cell–cell contact and mediated by conjugative plasmid-encoded proteins). F′ conjugative plasmids are F conjugative plasmids that have acquired, through recombination, a segment of DNA from the bacterial chromosome.

PHASE-VARIABLE PATHOGENS

Pathogenic microorganisms (both bacterial and eukaryotic) that evade the host immune system by frequent variation of their surface components (proteins, carbohydrates and lipids), called phase variation. The phase variations can be promoted by genetic changes, including mutation and recombination.

EPISOME

A replicon that can exist either extrachromosomally or when integrated into the bacterial chromosome.

REGRESSED REPLICATION FORK

A replication fork that, upon pausing (stalling) of replication, isomerizes such that the newly synthesized daughter strands base-pair with each other (not the templates on which they were synthesized).

DNA GYRASE

An enzyme that relieves supercoiling in DNA by creating a transient break in the double helix.

TEMPLATE SLIPPAGE

A model for the mechanism of frameshift mutation in which a DNA polymerase jumps to an incorrect next place on the template DNA during synthesis, thereby either adding or deleting bases in the nascent strand, the complements of which were present in the template.

POLAR ALLELE

A mutant allele of a gene that decreases or eliminates the expression of additional gene(s) downstream. Polar alleles are common in prokaryotic operons (groups of genes transcribed in a single mRNA).

NUCLEOID

Region in prokaryotes in which the DNA is concentrated. Unlike a nucleus, it is not bound by a membrane.

CONJUGATIVE TRANSFER

A specific process by which proteins encoded by the conjugative plasmid DNA (transfer or Tra proteins) allow passage of conjugative plasmid DNA, and any DNA contiguous with it, into another bacterium.

TOPOISOMERASES

Enzymes of two types that can remove (or create) supercoiling in duplex DNA by creating transitory breaks in one (type I) or both (type II) strands of the sugar-phosphate backbone.

BACTERIOSTATIC

Capable of inhibiting bacterial growth (but not necessarily capable of killing bacteria).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosenberg, S. Evolving responsively: adaptive mutation. Nat Rev Genet 2, 504–515 (2001). https://doi.org/10.1038/35080556

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35080556

This article is cited by

Search

Advanced search

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