Endy:Algorithm for codon optimization for evolutionary stability

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Mechanisms of spontaneous mutation in E. coli

The genetic stability of engineered biological systems can be modulated by increasing or decreasing the susceptibility of the system to host mutational mechanisms. In E. coli, spontaneous mutations occur at a rate of about 6x10-10 per base pair per doubling and arise by a wide variety of mechanisms (Drake, 1991). The mechanisms can be grouped into two categories: (1) point mutations and frameshifts and (2) gross DNA rearrangements. Point mutations and frameshifts frequently occur as results of errors in DNA replication, specifically polymerase base selectivity, mismatch repair, and proofreading (Schaaper, 1993). Gross DNA rearrangements include deletions, inversions, duplications, and transpositions. These rearrangements are typically associated with direct or inverted repeats and are thought to involve recombination mechanisms (Balbinder, 1993, Whoriskey et al., 1991, Schofield et al., 1992).

There is little quantitative data describing the relative frequencies of the various mutation types. The most well studied example is mutations leading to loss of function of the lacI gene. In four separate studies, a total of about 1500 lacI - mutants were sequenced and their mutations were characterized (Schaaper and Dunn, 1991, Schaaper et al., 1986, Halliday and Glickman, 1991, Farabaugh et al., 1978). About 75% of the mutants gained or lost a particular sequence, TGGC, that is repeated in several positions in the gene. The remaining mutations were divided between deletions (10%), duplications (3%), insertions (<1%), and point mutations (12%). The point mutations were further characterized by specific base pair change, with the C:G to T:A transition found to be the most frequent. This is potentially not surprising as more recent work has shown that promoting cytosine deamination (e.g., C to T mutation) in the non-transcribed strand is a general property of transcription in E. coli and is dependent on the length of time the transcription bubble stays open during elongation (Beletskii et al., 2000). It should be noted that these are far from all of the mechanisms of mutagenesis in E. coli. In particular, many alternate mechanisms drive mutagenesis during SOS response to DNA damage, starvation-induced stationary phase, and in the presence of exogenous mutagens (Purmal et al., 1994, Hastings et al., 2004).

References

  • Beletskii, A., A. Grigoriev, et al. (2000). "Mutations induced by bacteriophage T7 RNA polymerase and their effects on the composition of the T7 genome." J Mol Biol 300(5): 1057-65.
  • Drake, J. W. (1991). "A constant rate of spontaneous mutation in DNA-based microbes." Proc Natl Acad Sci U S A 88(16): 7160-4.
  • Farabaugh, P. J., U. Schmeissner, et al. (1978). "Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli." J Mol Biol 126(4): 847-57.
  • Halliday, J. A. and B. W. Glickman (1991). "Mechanisms of spontaneous mutation in DNA repair-proficient Escherichia coli." Mutat Res 250(1-2): 55-71.
  • Hastings, P. J., A. Slack, et al. (2004). "Adaptive amplification and point mutation are independent mechanisms: evidence for various stress-inducible mutation mechanisms." PLoS Biol 2(12): e399.
  • Purmal, A. A., Y. W. Kow, et al. (1994). "Major oxidative products of cytosine, 5-hydroxycytosine and 5-hydroxyuracil, exhibit sequence context-dependent mispairing in vitro." Nucleic Acids Res 22(1): 72-8.
  • Schaaper, R. M., B. N. Danforth, et al. (1986). "Mechanisms of spontaneous mutagenesis: an analysis of the spectrum of spontaneous mutation in the Escherichia coli lacI gene." J Mol Biol 189(2): 273-84.
  • Schaaper, R. M. and R. L. Dunn (1991). "Spontaneous mutation in the Escherichia coli lacI gene." Genetics 129(2): 317-26.
  • Schaaper, R. M. (1993). "Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli." J Biol Chem 268(32): 23762-5.
  • Balbinder, E. (1993). "Multiple pathways of deletion formation in Escherichia coli." Mutat Res 299(3-4): 193-209.
  • Whoriskey, S. K., M. A. Schofield, et al. (1991). "Isolation and characterization of Escherichia coli mutants with altered rates of deletion formation." Genetics 127(1): 21-30.
  • Schofield, M. A., R. Agbunag, et al. (1992). "DNA inversions between short inverted repeats in Escherichia coli." Genetics 132(2): 295-302.
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