IONIZING RADIATION INDUCED MUTATION IN ENDOGENOUS GENES

隐性等位基因突变被认为是致病因素之一。 在癌症和其他遗传性疾病的发展中。电离 辐射会导致突变，这些突变往往会影响多个基因位点。 因此，辐射引起的损害可能有很高的“暴露”潜力。 预先存在的突变或通过产生多位点缺失，使 细胞对未来隐性突变的表型后果 变得半合子的等位基因。这项建议探索了 假设一种制剂导致突变表达的概率 隐性等位基因取决于其相对致病倾向 基因内突变(基因内突变)和多位点突变(导致 多个连续遗传位点的缺失或修改)损害。 四种试剂，伽马射线，2-氨基-N6-羟基腺嘌呤(AHA)，UVC 和4-(9-吖啶氨基)间甲磺酸(MAMSA)，其 预计会导致不同比例的基因内和多位点 病变，将是本研究的重点。建议的实验是 针对隐性基因表达突变模型的评估 等位基因，通过量化和分析基因内与 在纯合子、杂合子和半合子基因靶点上的多位点病变。 将确定所选制剂造成的损害范围，并 反复接触这些诱变剂对频率和 使纯合基因失活的病变的特征将是 分析过了。该方案中的模型假定多位点损伤 增加突变、癌症和其他遗传性疾病的风险 第二次突变事件。因此，这些调查的目标是 增进对可能支配相互作用的因素的理解 基因内病变和多位点病变之间的关系。

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.