Spectrum of spontaneous mutations in liver tissue oflacI transgenic mice

Abstract

The advent of transgenic technology has greatly facilitated the study of mutation in animals in vivo. The Big Blue mouse system, transgenic for the lacI gene, permits not only the quantification of mutations in different tissues but also provides for the generation of in vivo-derived mutational spectra. This report details the sequence alterations of 348 spontaneous mutations recovered from the liver of 6-8-week-old male Big Blue mice. The spectra recovered from two strains of mice, C57BI/6 and B6C3F1, were compared and found to be very similar. The predominant mutations are G:C-->A:T transitions, with 75% of these occurring at 5'-CpG-3' sequences. This mutational bias is consistent with deamination-directed mutation at methylated cytosine bases. The second most common class of mutations is G:C-->T:A transversions. A significant clonal expansion of mutants was found in several animals, and this was used to make an approximate correction of the mutant frequency such that the most conservative estimate of mutation frequency is presented. The establishment of this substantial database of spontaneous mutations in the liver of Big Blue mice is intended to serve as a reference against which mutations recovered after treatment can be compared.