Induction Kinetics and Genetic Analysis of X-Ray-Induced Mutations in the Ad-3 Region of Neurospora Crassa

Webber, B. B.; Serres, Frederick J. de

doi:10.1073/pnas.53.2.430

Cited by 54 publications

(9 citation statements)

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“…These observations support the linear quadratic model based on the idea that the damage induced by low LET radiations is composed of a one hit nonrepairable component and a second component resulting from the interaction of two repairable events. This model has successfully explained mutation induction in different systems [1,23,39].…”

Section: Recovery From Pld and Premutational Damagementioning

confidence: 95%

Inhibition of repair of premutational lesions in plateau phase Chinese hamster cells exposed to gamma radiation

Rao

Hopwood

1983

Radiat Environ Biophys

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Induction and repair of forward mutations to 8-azaguanine resistance were studied in gamma irradiated, plateau phase Chinese hamster ovary cells. Mutation induction increased with dose with a relatively low induction for doses below 4 Gy and a steep increase thereafter. A close correlation between the ability of radiation to induce both lethality and mutations in plateau phase cells was evident. Recovery from potentially lethal damage resulted in a significant decrease in mutation frequency suggesting the possible involvement of an error free repair pathway. Mutation response at the end of recovery period was approximately linear with a slope of 2 X 10(-5) mutants per viable cells per Gy. This difference as compared to the immediate plating response supports the involvement of two types of damage in the induction of mutations: the nonrepairable, single hit component and a repairable component resulting from the interaction of lesions. Post-irradiation nonlethal hyperthermic treatment (42.5 degrees C; 30 min) sensitized the cells to killing as seen by the thermal enhancement ratio of 1.37. Interaction of hyperthermia, however, did not alter the mutation frequency obtained on immediate plating. Both post-irradiation hyperthermia and incubation at 4 degrees C inhibited most of the recovery from potentially lethal damage and also the repair of premutational lesions. These treatments resulted in a mutation frequency decrease of only 10-15% as compared to 50% seen in cells which actively repaired potentially lethal damage. The temperature dependence for the repair of premutational lesions suggests that the process is mediated by metabolically active steps.

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Section: Recovery From Pld and Premutational Damagementioning

confidence: 95%

Inhibition of repair of premutational lesions in plateau phase Chinese hamster cells exposed to gamma radiation

Rao

Hopwood

1983

Radiat Environ Biophys

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“…Our experiment with X rays [Webber and de Serres, 1965; de Serres 199 1 a,b] shows that X-ray-induced ad-3 mutations result from both major classes: genelpoint mutations and multilocus deletion mutations. Genelpoint mutations increase linearly with X-ray dose and multilocus deletion mutations increase as the square of X-ray dose [de Serres, 1990bl.…”

Section: Dose-dependent or Dose-independentmentioning

confidence: 99%

“…The ability to obtain dose-response curves makes it possible to extrapolate from the high exposures, used in the laboratory on model systems, to the low exposures that may occur in nature on the human population. However, it is important to note that the spectra of induced specific-locus mutations may be different at low vs. high levels of exposure [Webber and de Serres, 1965;de Serres, 199 la,b]. Genetic characterization of specific-locus mutations is essential in determining the impact of successful transmission of induced mutations to F, progeny, and an understanding of the "ground rules" associated with heterozygous effects of specific-locus mutations resulting either from gene/point mutation or multilocus deletion mutations [de Serres, 1988a[de Serres, -c, 1990dde Serres et al, 1992a,b].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of spontaneous and induced specific‐locus mutation in the ad‐3 region of neurospora crassa: Utilization in genetic risk assessment

Serres

1992

Environ and Mol Mutagen

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Data from experiments on the induction of specific-locus mutations in model systems are utilized in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the following information is required: (1) spontaneous and induced forward-mutation frequencies, (2) dose-response curves for the overall induction of specific-locus mutations, (3) genetic characterization of spontaneous and induced mutations, and (4) dose-response curves for the different genotypic classes. Specific-locus assays in most eukaryote assay systems provide only portions of the information required for genetic risk assessment. In recognition of the need for a more comprehensive data base, a model system was developed for specific-locus studies in Neurospora crassa. The adenine-3 (ad-3) specific-locus assay was modeled after the 2 gene, morphological specific-locus assay in the dilute-short-ear region of the mouse, and it detects forward-mutations at two closely linked loci: ad-3A and ad-3B. The ad-3 assay system has provided precise dose-response curves not only for inactivation, but also the overall induction of ad-3 mutations. The utilization of this assay in experiments with radiation or chemical mutagens has provided a data base on the induction and genetic characterization of specific-locus mutations that is unique among eukaryotic organisms. In this assay, gene/point mutations, multilocus deletion mutations, and 3 different classes of multiple-locus mutations can be identified. The latter consist of specific-locus mutations associated with recessive lethal mutations located either closely linked to the ad-3 region or elsewhere in the genome. The overall data base on the heterozygous effects of X-ray-induced ad-3 mutations demonstrates that such effects are allele specific, genotype specific, and locus specific. There are probably a variety of mechanisms by which the heterozygous effects of individual allelic mutations at different genetic loci can be affected. In conclusion, unless the frequencies of all of the different classes of induced specific-locus mutations are determined, and utilized in genetic risk assessment exercises, the risk of human exposure to environmental mutagens may be grossly underestimated.

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“…Experiments with X-rays (13,26,37) have shown that X-rayinduced ad-3 mutations result from both major classes, gene/point mutations and multilocus deletion motions, but that the percentages ofad-3 mutations in each class is dose-dependent over a wide range ofsurvivals and forward-mutation frequencies.…”

Section: Spectrum Of Ad-3 Mutations Can Be Dose Dependent or Dose-indmentioning

confidence: 99%

“…In recognition ofthe need for a specific-locus assay system that could provide the type ofdata required to permit a comprehensive genetic risk assessment, a new model system was developed with Neurospora crassa (12)(13)(14). The ad-3 assay was modeled after the dilute-short-ear (dse) morphological specific-locus assay in the mouse, developed by Russell (4).…”

Section: Introductionmentioning

confidence: 99%

Genetic risk assessment and specific-locus mutations in the ad-3 region of Neurospora crassa.

Serres

1994

Environ Health Perspect

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Data from experimentson the induction ofspecific-locus mutations in model systems are used in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the fMolwin information is required: a) spontaneous and induced forward-mutation frequencies, b) dose-response curves for the overall induction ofspecific-locus mutations, c) genetic characterization ofspontaneous and induced mutations, and d) dose-response curves forthe different genotypic classes. Specific-locus aaysin most eukaryote assay systems provide only portions ofthe information required for such assessments. In recognition ofthe need for more detailed information for risk assent, a model system has been developed for specific-locus assays in Neurospora crussa. The adenine-3 (ad-3) specific-locus assay was modeled after the two-gene morphological specific-locus assay in the dilute-short-ear region of the mouse and detects forward-mutations at two closely linked loci: ad-34 and ad-3B. A computerized data management program has made it possible to obtain precise dose-response curves not only for the overall induction ofad-3 mutations, but also for various genotypic subclasses. In addition, computerized statistical programs have been developed to compare dose-response curves. These methods of analysis have shown that the overall dose-response curve for specific-locus mutations in the ad-3 region is a composite ofmany different genotypic subclasses. In addition, these subclasses may have very different induction kinetics from those of the overall dose-response curve for ad-3 mutations.

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Induction Kinetics and Genetic Analysis of X-Ray-Induced Mutations in the Ad-3 Region of Neurospora Crassa

Cited by 54 publications

References 11 publications

Inhibition of repair of premutational lesions in plateau phase Chinese hamster cells exposed to gamma radiation

Inhibition of repair of premutational lesions in plateau phase Chinese hamster cells exposed to gamma radiation

Characteristics of spontaneous and induced specific‐locus mutation in the ad‐3 region of neurospora crassa: Utilization in genetic risk assessment

Genetic risk assessment and specific-locus mutations in the ad-3 region of Neurospora crassa.

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