Somatic and germinal mutations can have severe impacts on the fitness of multi-cellular organisms and their offspring. To understand these adverse effects important questions need to be answered. They are: 1) kinetics of mutation induction in relation to organ specificity, 2) mutation induction during development, 3) systemic effect of somatic mutations on age-related degenerative diseases, and 4) tumor progression from pre-neoplastic to neoplastic growth in relation to genomic stability. Presently the emphasis is on the study spontaneous and induced mutation mechanism in male germinal cells. The knowledge in this area is very limited, necessitate that the initial questions are basic such as: 1) Are there differences between the spontaneous and induced mutation frequencies in somatic and male germinal cells? And 2) what are the classes of chemicals that can induce mutations in male germinal cells? Our ability to study these questions concerning mutations in higher organisms has been limited by available methods. The use of transgenic systems that are based on recoverable vectors with targets for mutation detection may provide the tools to make these studies feasible. Transgenic mice on the C57Bl/6J background were produced using the phiX174 am3, cs70 vector. Two different mutational targets have been developed in the vector. They are 1) reversions of am3 (a single base pair substitution) and 2) forward mutations in gene A of phiX174 (21 different base pair substitution sites have been identified). Two other mutational targets are under development (frameshift system and another forward mutation system). A single burst assay (SBA) that directly distinguishes between mutations that are fixed in the animal (in vivo) and mutations that arise from in vivo or in vitro DNA damage have been developed and verified. The phiX system is the only transgenic system where the origin of mutations can be directly identified. This capability enhances its utility as a mammalian mutation system. Although most of the work until now has been based on studies of mutation detection in somatic tissues. These studies should be considered preliminary for the final goal to develop an accurate mutation system that can measure and characterize base pair substitutions induced in the male germinal cells.
