Spontaneous Mutations in Digestive Tract of Old Mice Show Tissue-Specific Patterns of Genomic Instability

Abstract

In an attempt to evaluate the possible role of mutations in the agedependent increase of tumor incidence, we studied the mutational burden that accumulates in the aging process in different parts of the digestive tract in mice. The mutations were monitored in lacZ genes integrated in the mouse genome. The digestive tract was divided into the esophagus, stomach, proximal, medial, and distal part of the small intestine, and the colon. Epithelial tissues were separated from these tissues with the exception of the esophagus, in which case the whole tissue was examined. At a young age, the mutant frequencies as well as the molecular nature of the mutations were similar among the tissues examined. In old age, on the other hand, mutant frequencies were elevated to different degrees among the tissues; they were high in the small intestine and colon, intermediate in the stomach, and low in the esophagus. The molecular characteristics of the mutations also revealed distinct tissue-specificity; there were elevated rates of a small deletion mutation in the esophagus, G:C to T:A transversion in the proximal small intestine, and multiple mutations in the distal small intestine and colon. The results indicate that different parts of the digestive tract suffer from different kinds of mutational stress in the aging process. The nature of the multiple mutations suggests the presence of a mutator phenotype based on an imbalance in deoxyribonucleotide pools.

The Maintenance of Genome Integrity is Tissue-Specific

“…Similar studies have been done with 10 other tissues and they are summarized in Fig. 3 (17,18). Mutants accumulate most rapidly in the epithelial tissues of the small and large intestine resulting in a 5-to 6-fold increase in mutant frequencies during 2 to 23 months of age.…”

“…Epithelial tissue in the proximal small intestine in old mice revealed a rise of G:C to T:A events. A similar tendency was also observed in the medial part of the small intestine (17). Since this type of mutation is known to be induced by oxidized guanine (8OHG), a possible cause could be an elevated level of this type of damage in the tissue, or an insu‹cient level of activity of the repair gene Ogg1 which is responsible for the removal of 8OHG (26).…”

“…The mutant frequencies show a wide range in middle age and old age mice. (17,18) This suggests that genome maintenance and repair systems vary among the diŠerent tissues. The genomes in epithelial tissues in the small and large intestine were the least protected among the tissues examined, while the genomes in brain, skin and testis were highly protected.…”

“…Comparison of mutation spectra of the esophagus between young and old animals reveals an elevation of deletion type mutations in old mice. Since most of the deletion mutations are single base deletions in repeated sequences (17), it is likely that the mismatch repair system which is responsible for repairing this type of damage could be insu‹cient in the esophagus. A comparison of the mutation spectra in the proximal small intestine shows a speciˆc increase of G:C to T:A mutations.…”

MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis

“…Moreover, the age of mice examined would also contribute to the difference because we found no histologic abnormalities in 12-month-old mice but a significant number of tumors in 18-month-old mice (19). It has been reported that the incidence of G:C to T:A transversions increases significantly in the intestines of older mice compared with younger mice (26,27). Because this transversion is mainly caused by oxidative DNA damage such as 8-oxoG lesions, these observations indicate that the mutations caused by this damage would tend to accumulate in the intestines during the course of aging.…”