THE IMPRINT OF SOMATIC HYPERMUTATION ON THE REPERTOIRE OF HUMAN GERMLINE-V GENES

In the human immune system, antibodies with high affinities for antige n are created in two stages. A diverse primary repertoire of antibody structures is produced by the combinatorial rearrangement of germline V gene segments and antibodies are selected from this repertoire by bi nding to the antigen. Their affinities are then improved by somatic hy permutation and further rounds of selection. We have dissected the seq uence diversity created at each stage in response to a wide range of a ntigens. In the primary repertoire, diversity is focused at the centre of the binding site. With somatic hypermutation, diversity spreads to regions at the periphery of the binding site that are highly conserve d in the primary repertoire. We propose that evolution has favoured th is complementarity as an efficient strategy for searching sequence spa ce and that the germline V gene families evolved to exploit the divers ity created by somatic hypermutation. (C) 1996 Academic Press Limited