Comparison of somatic mutation in a transgenic versus host locus

Abstract

Somatic mutations can now be quantified in almost any cell type in mice carrying bacterial genes in a lambda phage shuttle vector. Mutations induced in vivo are detectable ex vivo, after packaging host-cell DNA into phage that are grown on suitable bacteria. However, the transgenic DNA differs from many host loci in several ways: it (i) is prokaryotic DNA, (ii) is present in multiple tandem copies, and (iii) is heavily methylated and probably not expressed. Thus, mutation of a transgene may not be a suitable model of the host loci, which are eukaryotic, unique, and expressed. To test the relevance of the transgene mutation model, the frequencies of the bacterial lacI+ to lacI- mutations induced in half of the small intestine were compared with the frequencies of the host Dlb-1b to Dlb-1a mutations induced in the other half. The loci responded similarly to ethyl nitrosourea (ENU) with respect to the animal's age and sex, sex of the parent transmitting the transgene, and expression time. ENU dose-response curves were similar. Furthermore, no difference was found at the Dlb-1 locus between transgenic and nontransgenic siblings. In contrast, x-rays induced few lacI mutations but many Dlb-1 mutations. Probably few large deletions are detectable at lacI, but many are detectable at Dlb-1. If so, an important class of mutation is not readily detected in these transgenic mice. With this exception, the transgene and host gene responded similarly in this somewhat limited trial, as is necessary if the transgenic mice are to be a useful model.