Immunoglobulin (Ig) genes are first modified through the V(D)J (V, variable; D, diversity; J, joining) recombination process in pre–B cells. The Rag1/Rag2-dependent V(D)J recombination generates a large repertoire of B lymphocytes, each expressing a unique antibody molecule. Rearranged Ig genes are further modified by the somatic hypermutation process in activated germinal center B lymphocytes. Through somatic hypermutation, point mutations are introduced into Ig genes at the average frequency of one mutation/10 2 base pairs. After the mutation process, B cells with nucleotide substitutions resulting in higher affinity antibody are selected for proliferation and differentiation into memory or plasma cells.
Several molecular features are characteristic of somatic hypermutation (1). The mutations are mostly single substitutions, very rarely deletions or insertions. Hot spots of mutation have been observed and of these most notable are the AGY trinucleotides. Somatic mutation of Ig genes is confined to a region of ∼1.5...
