DIVERSIFICATION OF RABBIT V-H GENES BY GENE-CONVERSION-LIKE AND HYPERMUTATION MECHANISMS

Where, when and how does V-H diversification occur in the rabbit? Earl y diversification by gene-conversion and somatic hypermutation in rabb it appendix and chicken bursa of Fabricius are similar processes; the chicken bursa and the rabbit appendix have homologous functions. Howev er, diversification in bursa starts during embryonic development where as it starts in rabbit appendix about 2 weeks after birth in the prese nce of antigens and superantigens that may contribute to positive and negative selection, affect B-cell expansion and mold the repertoire. T he biochemical steps leading to diversification by gene conversion are unknown. However elevated levels of RAD51 mRNA in both chicken bursa and young rabbit appendix suggest that repair of double strand breaks may be involved. The base changes found in expressed rabbit V-H sequen ces derived from rearrangement of known germline V-H genes followed by one or more gene conversions occur with frequencies similar to those found in analyses of somatic hypermutation. The Ser codons in CDR1 and CDR2 of rabbit V(H)1 genes are all AGY rather than TCN, suggesting th at they may represent intrinsic hotspots for hypermutation comparable to those described in human and mouse V-H. Somatic hypermutation may f urther refine antibody affinities in rabbit germinal centers.