Through a glass, darkly: reflections of mutation from lacI transgenic mice.

The study of mutational frequency (Mf) and specificity in aging Big Blue lacI transgenic mice provides a unique opportunity to determine mutation rates (MR) in vivo in different tissues. We found that MR are not static, but rather, vary with the age or developmental stage of the tissue. Although Mf increase more rapidly early in life, MR are actually lower in younger animals than in older animals. For example, we estimate that the changes in Mf are 4.9x10(-8) and 1.1 x 10(-8) mutations/base pair/month in the livers of younger mice (<1. 5 months old) and older mice (> or =1.5 months old), respectively (a 4-fold decrease), and that the MR are 3.9 x 10(-9) and 1.3 x 10(-7) mutations/base pair/cell division, respectively ( approximately 30-fold increase). These data also permit an estimate of the MR of GC --> AT transitions occurring at 5'-CpG-3' (CpG) dinucleotide sequences. Subsequently, the contribution of these transitions to age-related demethylation of genomic DNA can be evaluated. Finally, to better understand the origin of observed Mf, we consider the contribution of various factors, including DNA damage and repair, by constructing a descriptive mutational model. We then apply this model to estimate the efficiency of repair of deaminated 5-methylcytosine nucleosides occurring at CpG dinucleotide sequences, as well as the influence of the Msh2(-/-) DNA repair defect on overall DNA repair efficiency in Big Blue mice. We conclude that even slight changes in DNA repair efficiency could lead to significant increases in mutation frequencies, potentially contributing significantly to human pathogenesis, including cancer.