A model for the molecular requirements of immunoglobulin heavy chain class switching

Heavy chain immunoglobulin gene expression requires two independent DNA recombination systems 1–3 . The first DNA rearrangement event (V–D–J recombination) involves the formation of a complete variable region (V H ) gene in pre-B lymphocytes 3–6 . The second series of recombination events allows for a switch in heavy chain constant region class from μ to either γ 3, γ 1, γ 2b, γ 2a, ɛ or α 1–3 . These recombination events occur in intervening sequences but do not alter or generate new coding information which is a common feature of V–D–J unions 1–3 . Tandemly repeated DNA sequences, spanning ∼2–5 kilobases (b), are localized ∼1.5 kilobase pairs 5′ of each C H gene and have been termed C H switch (S) regions. 2,7 . Two short, simple sequences that are shared by all switch region repeats (GAGCT and GGGGT) have been proposed to facilitate C H switching by homologous DNA recombination 8 . Unlike other switch regions, a large portion of the S μ region (3 kb) consists of essentially pure tandem repeats of GAGCT which are occasionally interrupted by a GGGGT 8 . However, the precise sites of switch-recombination in S μ are generally located considerably 5′ of this genetically unstable stretch 9,10 of GAGCT repeats (Fig. 1). We now report the properties of a novel C H S region sequence, YAGGTTG, which is 5′ of switch recombination sites and preferentially repeated in S regions.