SPONTANEOUS MUTATIONS IN A LACZ TRANSGENE AND IN RELATION TO DEVELOPMENT & AGING

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It has been hypothesized that somatic mutations are a major causal factor in aging and age-related diseases such as cancer and atherosclerosis. Recently, shuttle vector-based transgenic mouse models have been developed that allow accurate quantitation and characterization of mutations in vivo. The broad long-term objective of this proposal is to use these mouse models to obtain more insight in mutation frequency and their mechanism of induction in relation to development and in vivo aging. The specific aim of this project is to determine spontaneous and induced mutation spectra in several organs and tissues of mice from different transgenic strains at different age-levels including embryogenesis. The transgenic mouse model systems used throughout this project are different CD2 and C57B1/6-based lines harboring LacZ mutational target genes in bacteriophage lambda and plasmid vectors. These vectors are integrated in a head-to-tail arrangement, for each line at a different site in the genome. Spontaneous mutation frequency will be determined in suitable bacterial hosts using established procedures; a representative part of the mutants obtained will be further characterized by sequencing.