Following productive V gene rearrangement, the functional immunoglobulin genes in the B lymphocytes of man and mouse are subjected to two further types of genetic modification. Class-switch recombination, a region-specific but largely nonhomologous recombination process, leads to a change in constant region of the expressed antibody. Somatic hypermutation introduces multiple single nucleotide substitutions in and around the rearranged V gene segments and underpins affinity maturation. However, in chicken and rabbits (but not man or mouse), an additional mechanism, gene conversion, is a major contributor to V gene diversification . It has been demonstrated recently that both switch recombination and hypermutation are ablated in mice and humans lacking AID, a B cell-specific protein of unknown molecular activity [2-4]. Here we show that disruption of AID in the DT40 chicken B cell lymphoma leads to a failure to perform immunoglobulin V gene conversion. Thus, AID is required for all three immunoglobulin gene modification programs (gene conversion, hypermutation, and switch recombination) and acts in the initiation or execution of these processes rather than in bringing the B cell to an appropriate stage of differentiation.
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We thank Richard Grenfell for assistance with cell sorting, and we thank Gareth Williams and Rupert Beale for the partial AID cDNA clone and the 3′RACE product, respectively. R.S.H. was the recipient of a Burroughs Wellcome Fund Hitchings-Elion fellowship, and S.K.P.M. was the recipient of an EMBO fellowship. This work was supported in part by grants from the Arthritis Research Campaign and the Leukaemia Research Fund.