Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine

Somatic mutation accumulation has been implicated as a major cause of cance r and aging. By using a transgenic mouse model with a chromosomally integra ted lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., th e heart and small intestine. At young age the spectra were nearly identical , mainly consisting of GC to AT transitions and l-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G.C to T.A, G.C t o C.G. and A.T to C.G transversions and G.C to A.T transitions. In contrast , in heart about half of the accumulated mutations appeared to be large gen ome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Vir tually all other mutations accumulating in the heart appeared to be G.C to A.T transitions at CpG sites. These results suggest that distinct mechanism s lead to organ-specific genome deterioration and dysfunction at old age.