Theoretical Basis of Mutagenesis

  • F. E. Würgler
Part of the Environmental Science Research book series (ESRH, volume 31)


Mutations are changes in the hereditary material which are propagated throuah successive generations in cells and whole organisms. Mutations can occur spontaneously or under the influence of physical and chemical mutagenic agents. Depending on the type and size of the change in the genome we distinguish: point or gene mutations (base pair substitutions, frameshift mutations, small deletions), chromosome mutations or aberrations (e. g. , large deletions, translocations), aneuploidy (trisomy, monosomy, etc. ) and genome mutations (polyploidy). All these types of mutations are known to occur in man. Their phenotypic consequences can, even within one class of mutation, vary from lethality, malformations, and metabolic disorders to mild or even hardly detectable changes. Estimates suggest that a minimum of 10–11% of all live born will manifest at birth, or during development, or later in adulthood, a very wide range of serious genetic defects.

The mechanisms by which mutations are induced by mutagens are only poorly understood. A number of model systems (e.g., bacteria, fungi, insects, mammalian cells in culture) are suitable to study particular aspects of mutagenesis in prokaryotic and eukaryotic (nucleosomal) chromosomes.

In wild-type cells the induced frequency of a given type of mutation is the result of a complex interaction between normal DNA replication, error-free and error-prone DNA repair activities, and recombinational events. In some cases, in which the genetic control of the crucial steps is known (e.g., the rec-lex-dependent error-prone repair in E. coli), detailed and experimentally testable models could be worked out. In other cases (e.g., the induction of sister chromatid exchanges or chromosomal aberrations in eukaryotes) the models are less detailed. Some reasons for this are: the low number of suitable mutants available; multiple types of mutations induced by one particular mutagen; and difficulty in identifying the premutational lesion(s), particularly because of the insensitivity of the available biochemical assays. The complexity of the chemical mutagenesis is also reflected in the observation that differnt mechanisms can lead to the same type of mutation, e.g., the induction of chromosome aberrations is dependent on the normal S-phase DNA-synthesis with some agents but not with others. In addition, not only primary DNA damage (such as strand breaks, covalently bound mutagens, intercalations) but also non-DNA damage (e.g., effects of metals on the enzymes of DNA-synthesis, or interaction of spindle poisons with the polymerization of microtubules, or nucleotide pool imbalances) can lead to mutations.

A discussion of some models of the productions of different types of mutation illustrates our present knowledge on basic mutation mechanisms in pro- and eukaryotes. The importance of the knowledge of these mechanisms for genetic toxicology has to be stressed. Vfe can learn more about the types of lesions for which we should look in mutagenicity screening tests, and we can approach the construction of better defined and more sensitive test systems and test batteries.


Chromosome Aberration Frameshift Mutation Single Strand Break Inversion Chromosome Base Pair Substitution 
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  1. 1.
    Abbott, P. J. and R. Saffhill (1977) DNA synthesis with methylated poly (dA-dT): possible role of 0-methylthymidine as a promutagenic base.Nucleic Acids Res. 4: 761 – 769.Google Scholar
  2. 2.
    Abbott, P. J. and R. Saffhill (l979) DNA synthesis with methylated poly (dC-dG) templates: evidence for a competitive nature to miscoding by 0-methylguanine.Biochim.Biophys.Acta562:51–61.Google Scholar
  3. 3.
    Adler, I. D. Tl978) The cytogenetic heritable translocation test.Biol.Zentralblatt97:441–451.Google Scholar
  4. 4.
    Adolph, K. W. (1981) A serial sectioning study of the structure of human mitotic chromosomes.Eur.J.Cell Biol. 24: 146 – 153.Google Scholar
  5. 5.
    Albert, B. and R. Sternglanz (1977) Recent excitement in the DNA replication problem.Nature(Lond) 269: 655 – 661.Google Scholar
  6. 6.
    Baimai, V. and S. Kitthawee (1981) A spontaneous tandem duplication in aDrosophilachromosome.Experiential. 37: 345 – 346.Google Scholar
  7. 7.
    Baker, B. S. , J. B. Boyd, A. T. Carpenter, M. M. Green, T. D. Nguyen, P. Ripoll and P. D. Smith (1976) Genetic controls of meiotic recombination and somatic DNA metabolism inDrosophila melanogaster.Proc.Natl.Acad.Sci. USA 73: 4140 – 4144.ADSGoogle Scholar
  8. 8.
    Banks, G. R. and G. T. Yarranton (1976) DNA polymerase fromUstilago maydis. 2. Properties of associated deoxyribonuclease activity.Eur.J.Biochem. 62: 143 – 150.Google Scholar
  9. 9.
    Becker, E. F. , B. K. Zimmerman and E. P. Geiduschek (1964) Structure and function of cross-linked DNA. 1. Reversible denaturation andBacillus subtilistransformation.J.Mol.Biol. 8: 377 – 391.Google Scholar
  10. 10.
    Bender, M. A. , H. G. Griggs and J. S. Bedford (1874) Mechanisms of chromosomal aberration production. III. Chemicals and ionizing radiation.Mutation Res. 23: 197 – 212.Google Scholar
  11. 11.
    Bessman, M. J. , N. Muzyczka, M. F. Goodman and R. L. Schnaar (1974) Studies on the biochemical basis of spontaneous mutation. II. The incorporation of a base and its analogue into DNA by wild–type, mutator and antimutator DNA polymerases.J.Mol.Biol. 88: 409 – 421.Google Scholar
  12. 12.
    Billen, D. (19691 Replication of the bacterial chromosome: location of new initiation sites after irradiation.J.Bacterid. 97: 1169 (1969).Google Scholar
  13. 13.
    Borisy, G. G. and E. W. Taylor (1967) The mechanism of action of colchicine.J.Cell.Biol. 34: 525 – 535.Google Scholar
  14. 14.
    Bridges, C. B. (1936) The Bar “gene” a duplication.Science38: 210 – 211.Google Scholar
  15. 15.
    Bridges, B. A. and R. P. Mottershead (1978) Mutagenic DNA repair inEscherichia coli. VII. Constitutive and inducible manifestations.Mutation Res. 52: 151 – 159.Google Scholar
  16. 16.
    Bruhin, A. (1955) Uber diepolyploidisierende Wirkung eines Samenbeizmittels.Phytopathol. Z. 23: 381 – 394.Google Scholar
  17. 17.
    Brutlag, D. and A. Romberg (1972) Enzymatic synthesis of deoxynucleic acid. XXXVI. A proofreading function for the 3’–5’ exonuclease activity in deoxyribonucleic acid polymerase.J.Biol.Chem. 247: 241 – 248.Google Scholar
  18. 18.
    Bukhari, A. I. , J. A. Shapiro and S. L. Adhya (1977)DNA Insertion Elements,Plasmids and Episomes. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, pp. 1 – 782.Google Scholar
  19. 19.
    Butler, P. J. G. and J. O. Thomas (1980) Changes in chromatin folding in solution.J.Mol.Biol. 140: 505 – 529.Google Scholar
  20. 20.
    Buttula, N. and L. A. Loeb (19767 On the fidelity of DNA replication.J.Biol.Chem. 251:982–986.Google Scholar
  21. 21.
    Ganpbell, A. M. (1962) Episomes.Adv.Genet. 11: 101 – 145.Google Scholar
  22. 22.
    Chang,L. M. S. (1977) DNA polymerase from bakers-yeast.J.Biol.Chem. 252: 1873 – 1880.Google Scholar
  23. 23.
    Comings/ D. E. (1972) Structure and function of chromatin.Adv.Hum.Genet. 3: 237 – 431.Google Scholar
  24. 24.
    Comings, D. E. (1978) Mechanisms of chromosome banding and inplication for chromosome structure.Ann.Rev.Genet. 12: 25 – 46.Google Scholar
  25. 25.
    Daune, M. P. and R. P. P. Fuchs (1977) Structural modification of DNA after covalent binding of a carcinogen.Collog.Int.CNRS, 256: 83.Google Scholar
  26. 26.
    Delius, H. and W. Worcel (1974) Electron microscopic visualization of the folded chromosome ofEscherichia coli.J.Mol.Biol. 82: 107 – 109.Google Scholar
  27. 27.
    Deutsch, W. A. and S. Linn (1979) DNA binding activity from cultured human fibroblasts that is specific for partially depurinated DNA and that inserts purines into apurinic sites.Proc.Natl.Acad.Sci.USA76: 141 – 144.Google Scholar
  28. 28.
    Dcwsett, A. P. and M. W. Young (1982) Differing levels of dispersed repetitive DNA among closely related species of Drosophila.Proc.Natl.Acad.Sci.USA79: 4570 – 4574.Google Scholar
  29. 29.
    Drake, J. W. (1969a) Mutagenic mechanisms.Ann.Rev.Genet. 3: 247 – 268Google Scholar
  30. 30.
    Drake J. W. (1969b) Comparative rates of spontaneous mutation.Nature221: 1132.Google Scholar
  31. 31.
    Drake, J. W. (1970)The Molecular Basis of Mutation. Holden-Day, San Francisco, pp. 1 – 273.Google Scholar
  32. 32.
    Drake, J. W. (1977) Fundamental mutagenic mechanisms and their significance for environmental mutagenesis,in:Progress in Genetic Toxicology, D. Scott, B. A. Brdiges and F. H. Sobels, (Eds. ), Elsevier/North Holland Press, Amsterdam-New York-Oxford, pp. 43 – 55.Google Scholar
  33. 33.
    Drake, J. W. and R. H. Baltz (1976) The biochemistry of mutagenesis.Ann.Rev.Biochem. 45: 11 – 37.Google Scholar
  34. 34.
    Dupraw, E. J. (1965) Macromolecular organization of nuclei and chromosomes - a folded fibre model based on whole-mount electron microscopy.Nature206: 338 – 343.Google Scholar
  35. 35.
    DuPraw, E. J. (1966T Evidence for a “folded-fibre” organization in human chromsomes. Nature 209:577–581.Google Scholar
  36. 36.
    DuPraw, E. J. (1968)Cell and Molecular Biology. Academic Press, New York-London.Google Scholar
  37. 37.
    Eigsti, O. J. and P. Dustin (1954)Colchicine in Agriculture, Medicine, Biology and Chemistry. The Iowa State College Press, Ames.Google Scholar
  38. 38.
    Evans, H. J. (1962) Chromosome aberrations induced by ionizing radiations.Int. Rev, cytol. 13: 221 – 321.Google Scholar
  39. 39.
    Evans, H. J. (1974) Effects of ionizing radiation on mammalian chromosomes in:Chromsomes and Cancer, J. German (Ed. ), John Wiley, New York, pp. 191 – 238.Google Scholar
  40. Evans, H. J. (1977) Molecular mechanisms in the induction of chromosome aberrations, in:Progress in Genetic Toxicology, D. Scott, B. A. Bridges and F. H. Sobels (Eds. ), Elsevier, North Holland, Amsterdam, New York, Oxford, pp. 57 – 74.Google Scholar
  41. 41.
    Evans, H. J. (1980) How effects of chemicals might differ from those of radiations in giving rise to geneticl ill– health in man, in:Progress in Environmenta 1 Mutagenesis, M. Alacevic (Ed. ), Elsevier/North Holland, Amsterdam, New York, Oxford, pp. 3 – 21.Google Scholar
  42. 42.
    Evans, H. J. and D. Scott (1964) Influence of DNA synthesis on the production of chromatid aberrations by X-rays and maleic hydrazide inVicia faba. Genetics 49: 17 – 38.Google Scholar
  43. 43.
    Ferreira, N. R. and A. Buoniconti (1968) Trisomy after colchicine therapy.Lancetii: 1304.Google Scholar
  44. 44.
    Ferreira, N. R. and O. Frota-Pessoa (1969) Trisomy after cholchicine therapy.Lanceti:1160–1161.Google Scholar
  45. 45.
    Finch, J. T. and A. Klug’ (1976) Solenoidal model for superstructure in chromatin.Proc. Natl. Acad. Sci. USA73: 1897 – 1901.ADSGoogle Scholar
  46. 46.
    Flamm, W. G. , N. J. Bernheim and L. Fishbein (1970) On the existence of intrastrand cross-links in DNA alkylated with sulfur mustard.Biochim. Biophys. Acta224: 657 – 659.Google Scholar
  47. 47.
    Freese, E. (1959a) The difference between spontaneous and base-analogue induced mutations of phage T4.Proc. Natl. Acad. Sci. USA45: 622 – 633.Google Scholar
  48. 48.
    Freese, E. (1959b) The specific mutagenic effect of base analogues on phage T4.J. Mol. Biol. 1: 87 – 95.Google Scholar
  49. 49.
    Freese, E. (1963) Molecular nechanisms of mutations, in:Molecular Genetics, J. H. Taylor (Ed. ), Plenum Press, New York, pp. 207 – 269.Google Scholar
  50. 50.
    Gaulden, M. E. and J. G. Carlson (1951) Cytological effects of colchicine in the grasshopper neuroblastin vitrowith special reference to the origin of the spindle.Exp. Cell. Res. 2: 416.Google Scholar
  51. 51.
    Gebhart, E. , G. Schwanitz and G. Hartwich (1969) Zy togenetische Wirkung von Vincristin auf menschliche Leukozytenin vivoundin vitro.Med. Klin. 51: 2366 – 2371.Google Scholar
  52. 52.
    Generoso, W. M. , W. L. Russell, S. W. Huff, S. K. Stout and D. G. Gosslee (1974) Effects of dose on the induction of dominant-lethal mutations and heritable translocations with ethyl methanesulfonate in male mice.Genetics77: 741 – 752.Google Scholar
  53. 53.
    Generoso, W. M. , K. T. Cain, S. W. Huff and D. G. Gosslee (1978) Heritable translocation test in mice, in:Chemical Mutagens Principles and Methods for Their Detection, A. Hollaender and F. J. deSerres (Eds. ), Plenum Press, New York, Vol. 5, pp. 55 – 77.Google Scholar
  54. 54.
    Gerchman, L. L. and D. B. Ludlum (1973) The properties of 06-methylguanine in templates for RNA polymrase.Biochim. Biophys. Acta308: 310 – 316.Google Scholar
  55. 55.
    Gersch, N. F. and D. O. Jordan (1965) Interaction of DNA with aminoacridines.J. Mol. Biol. 13: 138 – 156.Google Scholar
  56. Green, M. H. L. (1979T Mutagenic consequences of chemical reaction with DNA, in:Chemical Carcinogens and DNA, P. L. Grover (Ed. ), CRC Press, Boca Raton, Florida, Vol. II, pp. 95 – 132.Google Scholar
  57. 57.
    Green, M. M. (1959) Reverse mutation inDrosophilaand the status of the particulate gene.Genetica29: 1 – 38.Google Scholar
  58. 58.
    Green, M. M. (1982) Genetic instability inDrosophila melanogaster: Deletion induction by insertion sequences.Proc. Natl. Acad. Sci. USA79: 5367 – 5369.Google Scholar
  59. Grunberger, D. and I. B. Vfeinstein (1979) Conformational changes in nucleic acids modified by chemical carcinogens, in:Chemical Carcinogens and DNA, P. L. Grover (Ed. ), CRC Press, Boca Raton, Florida, Vol. II, pp. 59 – 93.Google Scholar
  60. 60.
    Hayes, W. (1968)The Genetics of Bacteria and Their Viruses, 2nd Edition, Blackwell Scientific Publications, Oxford, Edinburgh.Google Scholar
  61. 61.
    Hendler, S. , E. Furer and P. R. Srinivasan (1970) Synthesis and chemical properties of monomers and polymers containing 7 me thy 1 guanine and an investigation of their substrate or template properties for bacterial DNA or RNA polymerases.Biochemistry9: 4141 – 4153.Google Scholar
  62. 62.
    Henrich, R. T. , T. Nogawa and A. Morishima (1980) In vitro induction of segregational errors of chromosomes by natural cannabinoids in normal human lymphocytes.Environ. Mutagen. 2: 139 – 147.Google Scholar
  63. 63.
    Hertwig, R. (1903) Ueber die Korrelation von Zell und Kerngrosse und ihre Bedeutung fur die geschlechtliche Differenzierung und die Teilung der Zelle.Biol. Zbl. 23: 108.Google Scholar
  64. 64.
    Hibner, U. and B. M. Albers (1980) Fidelity of DNA replication catalysedin vitroon a natural DNA template by the T4 bacteriophage multi-enzyme complex.Nature285: 300 – 305.Google Scholar
  65. 65.
    Hoefnagel, D. (1969) Trisomy after colchicine therapy.Lanceti:1160.Google Scholar
  66. 66.
    Hollstein, M. , J. McCann, F. A. Angelosanto and W. W. Nichols (1979) Short–term tests for carcinogens and mutagens.Mutation Res. 65: 133 – 226.Google Scholar
  67. 67.
    Howard, B. D. and J. Tessman (1964) Identification of the altered bases in mutated single stranded DNA. II. In vivo mutagenesis by 5-BUdR and 2-AP.J. Mol. Biol. 9: 364 – 371.Google Scholar
  68. 68.
    Howard–Flanders, P. (1973) DNA repair and recombination.Brit. Med. Bull. 29: 226 – 235.Google Scholar
  69. 69.
    IARC (1979) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. International Agency for Research on Cancer, Lyon, IARC Monographs, Suppl. 1, pp. 1 – 71.Google Scholar
  70. 70.
    Isono, K. and J. Yourno (1974) Chemical carcinogens as frameshift mutations:SalmonellaDNA sequence sensitive to mutagenesis by polycyclic carcinogens.Proc.Natl.Acad.Sci. USA 71: 1612 – 1617.ADSGoogle Scholar
  71. 71.
    Jenkins, N. A. , N. G. Copeland, B. A. Taylor and B. K. Lee (1981) Dilute (d) coat color nutation of DBA/2J mice is associated with the site of integration of an ecotropic Mulv genome.Nature293: 370 – 374.Google Scholar
  72. 72.
    Kavenoff, R. and B. H. Zimm (1973) Chromosome-sized DNA molecules fromDrosophila. Chromosoma 41: 1 – 27.Google Scholar
  73. 73.
    Kelner, A. (1953) Growth, respiration and nucleic acid synthesis in UV-irradiated and in photo-reactivatedEscherichia coli. J. Bacteriol. 65: 252.Google Scholar
  74. 74.
    Kihlman, B. A. Tl964l The production of chromosomal aberrations by streptonigrin inVicia faba.Mutation Res. 1:54–62.Google Scholar
  75. 75.
    Kihlnan, B. A. , A. T. Natarajan and H. C. Andersson (1978) Use of 5-bromodeoxyuridine-labelling technique for exploring mechanisms involved in the formation of chromosomal aberrations. I. G2 experiments with root tips ofVicia faba. Mutation Res. 55: 85 – 120.Google Scholar
  76. 76.
    Kimball, R. F. (1978) The relation of repair phenomena to mutation induction in bacteria.Mutation Res. 55: 85 – 120.Google Scholar
  77. 77.
    Kirtikar, D. M and D. A. Goldthwait (1974) The enzymatic release of 06 -methy 1 guanine and 3-methyladenine from DNA reaction with the carcinogen N-methyl-N-nitrosourea.Proc. Natl. Acad. Sci. USA71: 2022 – 2026.Google Scholar
  78. 78.
    Kolata, G. B. (1980) Genes and cancer: The story of Wilms tumor.Science207: 970 – 971.Google Scholar
  79. 79.
    Romberg, A. (1979) Aspects of DNA replication.Cold Spring Harbor Symp. Quant. Biol. 43: 1 – 9.Google Scholar
  80. 80.
    Runz, B. A. (1982) Genetic effects of deoxyribonucleotide pool imbalances. Environ. Mutagen. 4: 695 – 725.Google Scholar
  81. 81.
    Labhart, P. , T. Roller and H. Wunderli (1982) Involvement of higher order chromatin structures in metaphase chromosome organization. Cell 30: 115 – 121.Google Scholar
  82. 82.
    Laurence, D. J. R. (1963) Chain breakage of deoxyribonucleic acid following treatment with lew doses of sulphur mustand.Proc. Royal Soc. A 271: 520 – 530.ADSGoogle Scholar
  83. 83.
    Lawley, P. D. (1966) Some effects of chemical mutagens and carcinogens on nucleic acids.Progr. Nucl. Acid. Res. Mol. Biol. 5: 89 – 131.Google Scholar
  84. 84.
    Lawley, P. D. and P. Brookes (1963) Further studies on the aklylation of nucleic acids and their constituent nucleotides.Biochem. J. 89: 127 – 138.Google Scholar
  85. 85.
    Lawley, P. D. , J. H. Lethbridge, P. A. Edwards and R. V. Shooter (1969) Inactivation of bacteriophage T7 by mono and bifunctional sulphur mustard in relation to cross–linking and depurination of bacteriophage DNA.J. Mol. Biol. 38: 181 – 198.Google Scholar
  86. 86.
    Lawley, P. D. , A. R. Cra thorn, S. A. Shah and B. A. Smith (1972) Biomethylation of deoxyribonucleic acid in cultured human tumor cells (Hela). Methylated bases other than 5- methylcytosine not detected.Biochem. J. 128: 133 – 138.Google Scholar
  87. 87.
    Lawley, P. D. , D. J. Orr, P. B. Farrrer and M. Jarman (1973) Reaction products from Nnne thyl-N-ni trosourea and DNA containing thymidine residues, gynthesis and identification of a new methylation product, 04 methylthymidine.Biochem. J. 135: 193 – 201.Google Scholar
  88. 88.
    Ledda, G. M. , A. Columbano, P. M. Rao, S. Rajalakshmi, S. Sarma, D. S. R. Sarma (1980)In vivoreplication of carcigogen-inodified rat liver DNA: increased susceptibility of 0-methylguanine compared to N-methylguanine in replicated DNA to S-l-nuclease.Biochem.Biophys.Res.Comm. 95:816–821.Google Scholar
  89. 89.
    Lefevre, G. (1976) A photographic representation and interpretation of the polytene chromosomes ofDrosophila melanogastersalivary glands, in:The Genetics and Biology of Drosophila, M. Ashburner and E. Novitski (Eds. ), Academic Press, New York, Vol. la, pp. 32 – 67.Google Scholar
  90. 90.
    Lejeune, J. , J. Lafourcade, R. Berger, J. Vialatte, M. Roeswillwald, P. Seringe, and R. Turpin (1963) Trois cas de deletion partielle du bras court d’un chromosome 5.C. R. Acad. Sci. (Paris) 257: 3098 – 3102.Google Scholar
  91. 91.
    Lerman, L. S. (1963) The structure of the DNA-acridine complex.Proc. Natl. Acad. Sci. USA49: 94 – 102.ADSGoogle Scholar
  92. 92.
    Lerman, L. S. (1966) Acridine mutagens and DNA structure.J. Cell. Comp. Physiol. 64 (Suppl. 1): 1 – 18.Google Scholar
  93. 93.
    Lindahl, T. (1976) New class of enzymes acting on damaged DNA.Nature256: 64 – 66.Google Scholar
  94. 94.
    Lindahl, T. and A. Andersson (1972) Rate of chain breakage at apurinic sites in double stranded DNA.Biochemistry11: 3618 – 3623.Google Scholar
  95. 95.
    Lindahl, T. and B. Nyberg (1972) Rate of depurination of native deoxyribonucleic acid.Biochemistry11: 3610 – 3618.Google Scholar
  96. 96.
    Liquori, A. M. , B. DeLerma, F. Ascoli, C. Botre, and M. Trasciatti (1962) Interaction between DNA and polycyclic aromtic hydrocarbons.J. Mol. Biol. 5: 521 – 526.Google Scholar
  97. 97.
    Livneh, Z. , D. Elad, and J. Sperling (1979) Enzymatic insertion of purine bases into depurinated DNAin vitro.Proc. Natl. Acad. Sci. USA76: 1089 – 1093.Google Scholar
  98. 98.
    Loeb, L. A. (1974) Eukaryotic DNA polymerases, in:The Enzymes, P. Boyer (Ed. ), Academic Press, New York, Vol. 10, pp. 173 – 209.Google Scholar
  99. 99.
    Loveless, A. (1969) Possible relevance of 0-alkylation of deoxyguanosine to mutagenicity and carcinogenicity of nitrosamines and nitrosamides.Nature223: 206 – 207.Google Scholar
  100. 100.
    Ludlum, D. B. (1970) The properties of 7 methyl guanine containing templates for RNA polymerase.J. Biol. Chem. 245: 477 – 482.Google Scholar
  101. 101.
    Lutz, W. (1979)in vivocovalent binding of organic chemicals to DNA as a quantitative indicator in the process of chemical carcinogenesis.Mutation Res. 65:289–356.Google Scholar
  102. 102.
    Luzzati, D. (1962) The action of nitrous acid on transforming desoxyribonucleic acids.Biochem. Biophys. Res. Comm. 9: 508 – 516.Google Scholar
  103. 103.
    Marsden, M. P. F. and U. K. Laemmli (1979) Metaphase chromosome structure: evidence for a radial loop model.Cell17: 849 – 858.Google Scholar
  104. 104.
    McCann, J. , E. Choi, E. Yamasaki, and B. N. Ames (1975) Detection of carcinogens as mutagens in the Salmonella, microsome test: Assay of 300 chemicals.Proc. Natl. Acad. Sci. USA72: 5135 – 5139.Google Scholar
  105. 105.
    McGhee, J. D. and G. Felsenfeld (1980) Nucleosome structure.Ann. Rev. Biochem. 49: 1115 – 1156.Google Scholar
  106. 106.
    McKusick, V. A. (1978)Mendelian Inheritance in Man, ( 5th edition ), The Johns Hopkins University Press, Baltimore, pp. 1 – 975.Google Scholar
  107. 107.
    Margison, G. P. , and P. J. O’Connor (1973) Biological implications of the instability of N-glycosidic bond of 3-metnyldeoxyadeonsine in DNA.Biochim. Biophys. Acta331: 349 – 356.Google Scholar
  108. 108.
    Margison, G. P. , M. J. Capps, P. J. O’Connor, and A. A. Craig (1973) Loss of 7 methylguanine from rat liver DNA after methylationin vivowith methyl methanesulfonate or dimethyl nitrosamine.Chem. Biol. Interact. 6: 119 – 124.Google Scholar
  109. 109.
    Margoliash, E. , and E. L. Smith (1956) Structural and functional aspects of cytochrome c in relation to evolution, in:Evolving Genes and Proteins, V. Bryson and H. J. Vogel (Eds. ), Academic Press, New York, pp. 221 – 242.Google Scholar
  110. 110.
    Marinus, M. G. , and N. R. Morris (1975) Pleiotropic effects of a DNA adenine methylation mutant (dam-3) inEscherichia coli. Mutation Res. 28: 15 – 26.Google Scholar
  111. 111.
    Maneghini, R. (1976) Gaps in DNA synthesis by ultraviolet light irradiated W 138 human cells.Biochim. Biophys. Acta425: 419 – 427.Google Scholar
  112. 112.
    Mildvan, A. S. , and L. A. Loeb (1979) The role of metal ions in the mechanisms of DNA and RNA polymerases.CRC Crit. Rev. Biochem. 6: 219 – 244.Google Scholar
  113. 113.
    Mufti, S. (1979) Mutator effects of alleles of phage T4 genes 32, 41, 44, and 45 in the presence of an antimutator polyerase.Virology94: 1 – 9.Google Scholar
  114. 114.
    Mutfi, S. , and H. Bernstein (1974) The DNA–delay mutants of bacteriophage T4.J. Virol. 14: 860 – 871.Google Scholar
  115. 115.
    Muzyczka, N. , R. L. Poland, and M. J. Bessman (1972) Studies on the biochemical basis of spontaneous mutation. I. A comparison of the deoxyribonucleic acid polymerase of mutator, antimutator and wild–type strains of bacteriophage T4.J. Biol. Chem. 247: 7116 – 7122.Google Scholar
  116. 116.
    Natarajan, A. T. , and G. Obe (1978) Molecular mechanisms involved in the production of chromosomal aberrations. I. Utilization ofNeurosporaendonuclease for the study of aberration production in G2 stage of the cell cycle.Mutation Res. 52: 137 – 149.Google Scholar
  117. 117.
    Natarajan, A. T. , G. Obe, A. A. van Zeeland, F. Palitti, M. Meijers and E. A. M. Verdegaal-Immerzeel (1980) Molecular mechanisms involved in the production of chromosomal aberrations. II. Utilization ofNeurosporaendonuclease for the study of aberration production by X-rays in G1 and G2 stages of the cell cycle.Mutation Res. 69: 293 – 305.Google Scholar
  118. 118.
    Neary, G. T. , J. R. K. Savage, and H. J. Evans (1964) Chromatid aberrations inTradescantiapollen tubes induced by monochromatid X-rays of quantum energy 3 and 1. 5 keV.Int. J. Radiat. Biol. 8: 1 – 19.Google Scholar
  119. 119.
    Neel, J. V. (1983) Frequency of spontaneous and induced “point” mutations in higher eukaryotes.J. Heredity74: 2 – 15.Google Scholar
  120. 120.
    Oeda, K. , T. Horiuchi, and M. Sekiguchi (1981) Molecular cloning of the uvr D gene ofEscherichia colithat controls ultraviolet sensitivity and spontaneous mutation frequency.Mol. Gen. Genet. 101: 227 – 244.Google Scholar
  121. 121.
    Oeda, K. , T. Horiuchi, and M. Sekiguchi (1982) The uvr D gene ofE. coliencodes a DNA-dependent AT Pase.Nature298: 98 – 100.Google Scholar
  122. 122.
    Ohno, S. (1970)Evolution by Gene Duplication, Springer-Verlag, Heidelberg, New York, pp. 1 – 160.Google Scholar
  123. 123.
    Okada, T. A. , and D. E. Comings (1980) A search for protein cores in chromosomes: is the scaffold an artifact?Am. J. Hum. Genet. 32: 814 – 832.Google Scholar
  124. 124.
    Orgel, L. E. (1965) The chemical basis of mutation.Advan. Enzymol. 27: 289 – 346.Google Scholar
  125. 125.
    Orgel, A. , and L. E. Orgel (1965) Induction of mutations in bacteriophage T4 with divalent manganese.J. Mol. Biol. 14: 453 – 457.Google Scholar
  126. 126.
    Paulson, J. R. , and J. K. Laemmli (1977) The structure of histone–depleted metaphase chromosomes.Cell12: 817 – 828.Google Scholar
  127. 127.
    Perry, P. , and H. J. Evans (1975) Cytological detection of mutagen–carcinogen exposure by sister chromatid exchange.Nature258: 121 – 125.Google Scholar
  128. 128.
    Prescott, D. M. (1970) The structure and replication of eucaryotic chromosomes, in:Advances in Cell Biology, D. M. Prescott, L. Goldstein and E. McConkey (Eds. ), Appleton-Century-Crofts, New York, pp. 57 – 117.Google Scholar
  129. 129.
    Radman, M. (1975) SOS repair hypothesis: Phenomenology of an inducible DNA repair which is accompanied by mutagenesis, in:Molecular Mechanisms for the Repair of DNA, Part A, P. C. Hanawalt and R. B. Setlcw (Eds. ), Plenum Press, New York, pp. 355 – 367.Google Scholar
  130. 130.
    Radman, M. , S. Spadari, and G. Villani (1978a) Mutagenesis and cell transformation by ultraviolet radiation: Many hypotheses for few results.Natl. Cancer Inst. Monogr. 50: 121 – 127.Google Scholar
  131. 131.
    Radman, M. , S. Boiteux, O. Doubleday, G. Villani, and S. Spadari (1978b) Making and correcting errors in DNA synthesis:in vitroand semi-in vivostudies of mutagenesis.J. Supramol. Struct12 (Suppl): 14.Google Scholar
  132. 132.
    Radman, M. , G. Villani, S. Boiteux, A. R. Kinsetta, B. W. Glickman, and S. Spadari (1979) Replication fidelity: mechanisms of mutation avoidance and mutation fixation.Cold Spring Harbor Symp. Quant. Biol. 43: 937 – 946.Google Scholar
  133. 133.
    Ramel, C. (1969) Genetic effects of organic mercury coirpounds. I. Cytological inviestigations onAlliumroots.Hereditas61: 208 – 230.Google Scholar
  134. 134.
    Ramel, C. (1972) Genetic effects, in:Mercury in the Environment, an Epidemiological and Toxicological Appraisal, L. Fridberg and I. Vostal (Eds. ),CRC Press, Boca Raton, Florida, pp. 169 – 181.Google Scholar
  135. 135.
    Ramel C. , and J. Magnusson (1969) Genetic effects of organic mercury compounds. II. Chromosome segregation inDrosophila melanogaster. Hereditas 61: 231 – 254.Google Scholar
  136. 136.
    Rapoport, J. A. (1940) Multiple linear repetitions of chromosome blocks and their evolutionary significance.J. Gen. Biol. (Moscow) 1: 235 – 270.Google Scholar
  137. 137.
    Richet, E. , R. Kern, M. Kobiyama, and M. Hirota (1980) Isolation of DNA-dependent ATPase I mutants of E. coli, in:Mechanistic Studies of DNA Replication and Genetic Recombination, B. Alberts (Ed. ), Academic Press, New York, pp. 606 – 608.Google Scholar
  138. 138.
    Reiger, R. , A. Michaelis, and M. M. Green (1968)A Gloccary of Genetics and Cytogenetics, Springer-Verlag, New York, pp. 1 – 647.Google Scholar
  139. 139.
    Ripley, L. S. (1975) Transversion mutagenesis in bacteriophage T4.Molec. Gen. Genet. 141: 23 – 40.Google Scholar
  140. 140.
    Ris, H. , and D. F. Kubai (1970) Chromosome structure.Ann. Rev. Genet. 4: 263 – 294.Google Scholar
  141. 141.
    Russell, L. B. (1964) Genetic and functional mosaicism in the mouse, in:Role of Chromosomes in Development, M. Locke (Ed. ), 23rd Symp. Soc. Develop, and Grcwth, Academic Press, New York.Google Scholar
  142. 142.
    Russell, L. B. (1976) Numerical sex-chromosome anomalies in mammals: Their spontaneous occurrence and use in mutagenesis studies, in:Chemical Mutagens-Principles and Methods for Their Detection, A. Hollaender (Ed. ), Plenum Press, New York, Vol. 4, 55 – 91.Google Scholar
  143. 143.
    Saffhill, R. , and P. J. Abbott (1978) Formation of 0-methylthymidine in poly (dA-dT) on methylation with N-methy-N-nitrosourea and dimethyl sulfate. Evidence that 02-methylthymidine does not miscode during DNA synthesis.Nucleic Acid Res. 5: 1971 – 1978.Google Scholar
  144. 144.
    Sarabhai, A. , A. D. W. Stretton, S. Brenner, and A. Bolle (1964) Colinearity of the gene with the polypeptide chain.Nature201: 13 – 17.Google Scholar
  145. 145.
    Sax, K. (1940) An analysis of X–ray induced chromosome aberrations inTradescantia. Genetics25: 41 – 68.Google Scholar
  146. 146.
    Scott, D. (1980) Molecular mechanisms of chromosome structural changes, in:Progress in Evironmental Mutagenesis, M. Alacevic (Ed. ), Elsevier/North-Holland, Amsterdam, New York, Oxford, pp. 101 – 113.Google Scholar
  147. 147.
    Scott, D. , and H. J. Evans (1964) On the non–requirement for deoxyribonucleic acid synthesis in the production of chromosome aberrations by 8-ethoxycaffeine.Mutation Res. 1: 146 – 156.Google Scholar
  148. 148.
    Scott, D. , and H. J. Evans (1967) X-ray-induced chromosomal aberrations inVicia faba: Changes in response daring the cell cycle.Mutation Res. 4: 579 – 599.Google Scholar
  149. 149.
    Sega, G. A. , and J. G. Owens [19787 Ethylation of DNA and protamine by ethyl methanesulfonate in the germ cells of male mice and the relevancy of these molecular targets to the induction of dominant lethals.Mutation Res. 52:87–106.Google Scholar
  150. 150.
    Sesnowitz-Horn, S. , and E. A. Adelberg Tl968) Proflavin treatment ofEscherichia coli: Generation of frameshift mutations.Cold Spring Harbor Symp.Quant.Biol. 33:393–402.Google Scholar
  151. 151.
    Shafer, D. A. (1977) Replication bypass model of sister chromatid exchanges and implications for Bloom’s syndrome and Fanconi’s anemia.Hum. Genet. 39: 177 – 190.Google Scholar
  152. 152.
    Sherman, C. W. , and L. A. Loeb (1977) Depurination decreases fidelity of DNA synthesisin vitro. Nature 270: 537 – 538.ADSGoogle Scholar
  153. 153.
    Sherman, C. W. , and L. A. Loeb (1979) Effects of depurination on the fidelity of DNA synthesis.J. Mol. Biol. 128: 197 – 218.Google Scholar
  154. 154.
    Shugar, D. , C. P. Huber, and G. I. Birnbaum (1976) Mechanism of hydroxylamine mutagenesis Crystal structure and confirmation of 1,5-dimethyl-N-hydroxy-cytosine.Biochim. Biophys. Acta447: 274 – 284.Google Scholar
  155. 155.
    Singer, 0–977) Sites in nucleic acids reacting with alkylating agents of differing carcinogenicity or mutagenicity.J.Toxicol.Environm.Health2:1279–1295.Google Scholar
  156. 156.
    Singer, B. , H. Fraenkel-Conrat, and J. T. Kusmiereck (1978) Preparation and template activities of polynucleotides containing 0 - and 0 -alkyl uridine.Proc. Natl. Acad. Sci. USA75: 1722 – 1726.Google Scholar
  157. 157.
    Sirover, M. A. , and L. A. Loeb (1980) On the fidelity of DNA synthesis: Effects of steroids and intercalating agents.Chem. -Biol. Interactions30: 1 – 8.Google Scholar
  158. 158.
    Smith, M. D. , R. R. Green, L. S. Ripley, and J. W. Drake (1973) Thyminless mutagenesis in bacteriophage T4.Genetics74: 393 – 403.Google Scholar
  159. 159.
    Stark, A. A. , J. M. Essigmann, A. L. Demain, T. R. Skopek, and G. N. Wogan (1979) Aflatoxin Bl mutagenesis, DNA binding, and adduct formation inSalmonella typhimurium. Proc. Natl. Acad. Sci. USA76: 1343 – 1347.ADSGoogle Scholar
  160. 160.
    Steffensen, D. M. (1962) A variable distance for chomosome exchange dependent on cellular activity, temperature and other conditions.Radiation Res. 16: 590.Google Scholar
  161. 161.
    Strauss, B. , and T. Hill (1970) The intermediate in the degradation of DNA alkylated with a monof unct ional alkylating agent.Biochim. Biophys. Acta213: 14 – 25.Google Scholar
  162. 162.
    Streisinger, G. , Y. Okada, J. Emrich, I. Newton, A. Tsugita, E. Terzaghi, and M. Inouye (1966) Frameshift mutations and the genetic code.Cold Spring Harbor Symp. Quant. Biol. 31: 77 – 84.Google Scholar
  163. 163.
    Stubblef ield, E. , and W. Wray (1971) Architecture of the Chinese hamster metaphase chromosome.Chromosoma32: 262 – 294.Google Scholar
  164. 164.
    Talmud, P. J. , and D. Lewis (1974a) Mutagenicity of amino-acid analogs inCoprinus lagopus.Genet. Res. 23: 47 – 61.Google Scholar
  165. 165.
    Talmud, P. J. , and D. Lewis (1974b) Mutagenicity of amino-acid analogs in eukaryotes.Nature249: 563 – 564.Google Scholar
  166. 166.
    Tessman, I. (1962) The induction of large deletions by nitrous acid.J. Mol. Biol. 5: 442 – 445.Google Scholar
  167. 167.
    Tessman, J. , R. K. Poddar, and S. Kumar (1964) Identification of the altered bases in mutant single stranded DNA. I.In vitromutagenesis by hydroxylamine, ethyl methanesulfonate and nitrous acid. J. Mol. Biol. 9: 352 – 363.Google Scholar
  168. 168.
    Therman, E. (1980)Human Chromosomes, Structure, Behavior, Effects, Springe-Verlag, New York, pp. 1 – 235.Google Scholar
  169. 169.
    Thoma, F. , and T. Koller (1981) Unravelled nucleosomes, nucleosome beads and higher order structures of chromatin: influence of non–histone components and histone Hi.J. Mol. Biol. 149: 709 – 733.Google Scholar
  170. 170.
    Thoma, R. , T. Koller, and A. Klug (1979) Involvement of histone Hi in the organization of the nucleosome and of the salt-dependent superstructures of chromatin.J. Cell. Biol. 83: 403 – 427.Google Scholar
  171. 171.
    Topal, M. D. , and J. R. Fresco (1967) Complementary base pairing and the origin of substitution mutations.Nature263: 285 – 289.Google Scholar
  172. 172.
    Van der Schans, G. P. (1969) On the production of breaks in DNA by gamma-rays.Int. J. Radiat. Biol. 16: 58.Google Scholar
  173. 173.
    Vig, B. K. , and R. Lewis (1978) Genetic toxicology of bleomycin.Mutation Res. 55: 121 – 145.Google Scholar
  174. 174.
    Vogel, F. , and A. G. Motulsky (1979)Human Genetics: Problems and Approaches, Springer-Verlag, Heidelberg, New York, pp. 1 – 700.Google Scholar
  175. 175.
    de Vries, H. (1901)Die Mutationstheorie, Bd. 1, Veit & Conp. , Leipzig.Google Scholar
  176. 176.
    Waring, M. J. (1965) Complex formation between ethidium bromide and nucleic acids.J. Mol. Biol. 13: 269 – 282.Google Scholar
  177. 177.
    Watson, J. D. , and F. H. C. Crick (1953) The structure ofCold Spring Harbor Symp. Quant. Biol. 18: 123 – 131.Google Scholar
  178. 178.
    Weigle, J. J. (1953) Induction of mutations in bacterial virus.Proc. Natl. Acad. Sci. USA39: 628 – 636.ADSGoogle Scholar
  179. 179.
    Weigle, J. J. , and R. Dulbecco (1953) Induction of mutations in bacteriophage T3 by ultraviolet light.Experientia9: 372 – 373.Google Scholar
  180. 180.
    Weinstein, I. B. , and D. Grunberger (1974) Structural and functional changes in nucleic acids modified by chemical carcinogens, in:Chemical Carcinogenesis, Part A, P. 0. P. T1 so and J. A. DiPaolo (Eds. ), Marcel Dekker, New York, pp. 217 – 235.Google Scholar
  181. 181.
    White, M. J. D. (1973)The Chromosomes, 6th Edition, Chapman and Hall, London.Google Scholar
  182. 182.
    Whitney, J. B. Ill, and M. L. Lamoreaux (1981) Transposable elements controlling genetic instabilities in mammals.J. Hered. 73: 12 – 18.Google Scholar
  183. 183.
    Wickner, S. , and J. Hurwitz (1974) Conversion of (f) X174 viral DNA to double-stranded form by purifiedEscherichia coliproteins.Proc. Natl. Acad. Sci. USA71: 4120 – 1424.Google Scholar
  184. 184.
    Witkin, E. M. (1967) Mutation-proof and mutation-prone modes of survival in derivatives of Escherichia coli B differing in sensitivity to ultraviolet light.Brookhaven Symp. Biol. 20: 17 – 55.Google Scholar
  185. 185.
    Witkowski, R. , and F. H. Herrmann (1976)Einführung in die Klinische Genetik, Vieweg, Braunschweig, pp. 1 – 218.Google Scholar
  186. 186.
    Wolff, S. (1977) Sister chromatid exchange.Ann. Rev. Genet. 11: 183 – 201.Google Scholar
  187. 187.
    Wolff, S. , and P. Perry (1975) Insights on chromosome structure from sister chromatid exchange ratios and the lack of both isolabelling and heterolabelling as determined by the FPG technique.Exp. Cell Res. 93: 23 – 30.Google Scholar
  188. 188.
    Wolff, S. , K. C. Atwood, M. L. Randolph, and H. E. Luippold (1958) Factors limiting the number of radiation induced chromosome exchanges. I. Distance: Evidence from noninteraction of X-ray and neutron-induced breaks.J. Biophys. Biochem. Cytol. 4: 365 – 372.Google Scholar
  189. 189.
    Yunis, J. J. (1976) High resolution of human chromosomes.Science191: 1268 – 1270.Google Scholar
  190. 190.
    Yunis, J. J. (1980) Nomenclature for high resolution human chromosomes.Cancer Genet. Cytogenet. 2: 221 – 229.Google Scholar
  191. 191.
    Zampieri, A. , and J. Greenberg (1965) Mutagenesis by acridine orange and proflavin inEscherichia coli strains S. Mutation Res. 2: 552 – 556.Google Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • F. E. Würgler
    • 1
    • 2
  1. 1.Institute of ToxicologySwiss Federal Institute of TechnologySwitzerland
  2. 2.University of ZürichSwitzerland

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