SPONTANEOUS MUTATIONS IN LACI-CONTAINING LAMBDA-LYSOGENS DERIVED FROMTRANSGENIC MICE - THE OBSERVED PATTERNS DIFFER IN LIVER AND SPLEEN

The pattern of somatic mutation observed in tumor suppressor genes, su ch as the p53 gene, vary dramatically with tumor type. Some of the obs erved differences are due to tissue specific effects of mutagens, but it is also possible that some differences may reflect the tissue/cell type specificity of spontaneous mutation. Transgenic mouse models with recombinant shuttle vectors containing the lad or lacZ target genes m ay shed light on the extent to which spontaneous mutation displays tis sue specificity. Herein we utilize a recently described selectable sys tem to obtain spontaneous mutants for analysis of the molecular lesion s. Spontaneous mutations were isolated in the lad gene recovered from five transgenic mice carrying a lambda shuttle vector. Seventy-three a nd 67 independent mutations derived from liver and spleen DNA, respect ively, were defined in the amino terminal region of lad. Although tech nical barriers preclude a direct assessment of the E. coli derived pat tern of mutation in this system, five pieces of circumstantial evidenc e suggest that many of the mutations arose in mouse rather than in E. coli. In DNA from both liver and spleen, mutations at CpG dinucleotide s predominate (58% and 51%, respectively). In spleen, most of the muta tions at CpG are transitions, while in liver most are transversions. I n addition, liver has a higher frequency of GC-->TA transversions at n on-CpG dinucleotides while spleen had a higher frequency of deletions and insertions. The data provide evidence that the spontaneous pattern of mutation is tissue specific. In addition, the high frequency of tr ansversions at CpG suggests the need to reevaluate the mechanisms by w hich mutations occur at this methylated dinucleotide.