Somatic hypermutation of variable (V) genes, which encode a portion of immunoglobulin molecules, occurs at a frequency that is a million times greater than mutation in other genes. The molecular mechanism that introduces these mutations is unknown. The project had two major aims. The first goal was to study hypermutation in mice deficient for DNA repair enzymes to see if the frequency and pattern of mutation was different from wildtype mice. The frequency of mutation in V genes from mice deficient for the nucleotide excision repair protein, XPA, and mismatch repair proteins, PMS2, MSH2, and MLH1, was similar to that of wildtype mice, indicating that neither of these repair pathways generates hypermutation. However, the pattern of mutation was altered in the mismatch repair-deficient mice compared to wildtype mice. The results suggest that the hypermutation pathway frequently introduces tandem mutations which are then corrected by a PMS2-dependent repair process, and frequently mutates G C basepairs which are then corrected by a MSH2-dependent pathway. The second goal was to analyze hypermutation in V genes from old and young humans to determine if the frequency or pattern of mutation changes with age. The frequency of mutation was identical in both groups, indicating that old humans have hypermutated antibodies with high affinity for antigens. The spectra of mutation in old humans was different than that of young humans, suggesting that mismatch repair decreases with age.
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