GENETIC VARIATION IN B LYMPHOCYTE ONTOGENY

University Of California San Francisco, San Francisco CA

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Abstract

Leading to cancer, aging, or both, somatic mutations are usually detrimental to the individual. Mutations at the immunoglobulin (Ig) loci are an exception, because they generate high affinity antibodies, which are important in memory responses to pathogens. Thus, in the segments of immunoglobulin genes that encode the variable (V) regions of antibodies, mutations are beneficial. Since such mutations arise at a million times higher rate than the normal, spontaneous mutation rate at other loci, the process is called hypermutation. Due to its high rate and to its being focused to a few loci, hypermutation allows easier access to the proximate causes of mutation and may thus serve as a model system for studies of the mutational process in general. Hypermutation is catalyzed by the putative immunoglobulin mutator system, or "mutator". This mutator is thought to put an imbalance onto the general DNA error repair system. The sequences that target the action of the mutator to the immunoglobulin locus ( enhancers) differ from the sequences where the mutator action is seen (the V (D) J segments and their flanking sequences). Furthermore, within the sequences to be mutated, there are short stretches that are even more mutable than the others, and these so-called hot spots may represent sequence motifs. The objective of this application is to define, in an in vitro transfection system as well as in vivo, cis and trans-acting element for hypermutation at the immunoglobulin loci. Specifically, (I) the role of the enhancer in the major intron as well as other other intronic sequences at the immunoglobulin heavy-chain locus will be defined; (ii) the target base pairs, or hot spot motifs, within the V regions will be identified; and (III) mutation frequencies and profiles will be assessed in monoclonal mice with and without a mismatch repair deficiency.