The Influence of Somatic Mutation on Clonal Expansion

Abstract

The key feature of the process of somatic diversification is that mutations accumulate sequentially during clonal expansion. This was first recognized from the hierarchy of shared mutations in antibodies from clonally related lymphocytes (McKean et al. 1984) and supported by the finding that the frequency of mutations increases during the immune response to antigen (Berek et al. 1985). Although the mechanism of mutation is still a mystery, one consequence is to introduce discrete point mutations into expressed V genes. This is readily observed among antibodies at initial stages of diversification when expressed V genes can differ from their germline counterparts by single base changes (Weigert et al. 1970) and among clonally related antibodies where siblings differ from each other by single base changes (for example, Radie et al. 1989). Thus the high frequency of mutations in Y genes of antibodies from the secondary response to antigen is likely due to the sequential accumulation of point mutations.