Targets of somatic hypermutation within IgH genes in zebrafish (P1080)

Abstract In mammals, somatic hypermutation (SHM) of IgH genes is critical for the generation of high affinity antibodies and effective immune responses. Knowledge of sequence specific biases in the targeting of mutations can be useful to understand antibody repertoires produced in response to infections, B cell neoplasms, or autoimmune disease. To evaluate potential nucleotide targets of SHM in zebrafish, we constructed a cDNA library of V(D)J_C segments from randomly selected clones which were sequenced and analyzed. Mutations were most prevalent in V regions with a bias towards single base transitions and increased mutation in complementarity determining regions. Mutations were overrepresented at WRCH/DGYW motifs suggestive of activation-induced cytidine deaminase (AID) targeting common in mice and humans. In contrast to mammals, AID hotspots were largely restricted to palindromic WRCH/DGYW motifs. Taken together, the data reveal specific nucleotide targets of SHM in zebrafish and suggest both AID and affinity maturation contributes to antibody diversification in this emerging immunological model.