Mutations at recessive alleles have been implicated as a causative factor in the development of cancer and other genetic diseases. Ionizing radiation causes mutations which often affect multiple genetic loci. Radiation-induced damage, therefore, may have a high potential to """"""""uncover"""""""" pre-existing mutations or by producing multilocus deletions, sensitize the cells to the phenotypic consequences of future mutations in recessive alleles which have become hemizygous. This proposal explores the hypothesis that the probability an agent will cause expression of mutations at recessive alleles is dependent on its relative propensity to cause intragenic (mutations within a gene) and multilocus (mutations resulting in deletion or modification of multiple contiguous genetic loci) lesions. Four agents, gamma radiation, 2-amino-N6-hydroxyadenine (AHA), UVC radiation, and 4-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA), which are expected to cause different proportions of intragenic and multilocus lesions, will be the focus of this study. Proposed experiments are directed toward evaluation of a model for expressed mutations at recessive alleles, through quantification and analysis of intragenic versus multilocus lesions at homozygous, heterozygous and hemizygous gene targets. The spectrum of damage caused by the selected agents will be determined and the effects of repeated exposure to these mutagens on the frequency and characteristics of lesions which inactivate a homozygous gene will be analyzed. The model in this proposal postulates that multilocus lesions enhance the risk for mutation, cancer and other genetic diseases from a second mutational event. Accordingly, the goal of these investigations is to augment the understanding of factors which may govern the interaction between intragenic lesions and multilocus lesions.
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