A detailed analysis of the genes and proteins that participate in the murine immune response to PC has provided key insights at the structural level into the phenomenon of somatic mutation in B cells. Most anti-PC antibodies are encoded by 1 VH gene of the S107 subfamily, and 3 VK genes, VKT15 of the VK22 subfamily, VKM3 from the VK8 subfamily, and VK167 from the VK24 subfamily. No mutation was detected in these genes until the 2nd wk after immunization, indicating that mutation is under developmental control. The protein sequences of 73 heavy and light chains derived from the secondary response support the concept of developmental activation of mutation after antigen stimulation. No mutation was found in the IgM antibodies, whereas half of the IgG and IgA antibodies had mutation. Most of the mutated antibodies had higher affinity for antigen than their germline counterparts, which suggests that the major role of somatic mutation is to increase affinity rather than to create new specificities. Nucleotide sequencing established two hallmarks of mutation in immunoglobulin genes: mutations are targeted to a 1 kilobase region surrounding and including the rearranged variable gene, and they occur at an extraordinary frequency of 10(-2) nucleotide substitutions. Mutation is probably caused by DNA repair, and may occur during error-prone repair of nicked DNA around the variable gene or during mismatch repair of misaligned structural intermediates. The elucidation of this remarkable mechanism clearly requires studies of a more dynamic character. Two major questions that need to be answered are: what targets mutation to the variable gene, and what enzymes are involved?