The goal of Project 6 on Genetics of Genomic Stability is to measure the frequency of somatic mutations in brain and liver DNA of UM-HET3 mice. Approximately 480 of the mice in Population 1 will be bred to carry one or both copies of an integrated lacZ plasmid pUR288 transgene previously used by Vijg et al. to document age-related increases in somatic mutation frequency in C57BL/67 mice. The data, when combined with the genotypes generated by genotyping core, will permit identification of loci that influences rates of somatic mutations in the liver-a tissue in which mutation frequency increases with age- and in brain, in which mutation frequency is age-insensitive. In addition, the system used will permit measurement of the distribution of large-scale (e.g. deletion) and small-scale mutations in the liver tissue from each individual animal, and thus to detect polymorphic loci that influence the relative and absolute rates of these two forms of somatic mutation. It will be informative to compare the mutation frequencies, and the relative proportions of large-scale to small-scale mutation in each mouse, with the results of measures of oxidative and glycoxidative damage (Project 5), and to determine whether those mice most prone to mutation accumulation show abnormal function in tissues dependent on constitutive or facultative cellular proliferation (Projects 1 and 3). Because the occurrence of somatic mutations has been hypothesized to contribute to neoplasia and other senescent phenotypes in mammals, it will be of particular interest to see in loci that influence the frequency of deletions or small-scale mutations are linked to those found to influence longevity and tumor incidence rates in UM-HET3 mice.
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