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

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Abstract

Heavy chain immunoglobulin gene expression requires two independent DNA recombination systems1–3. The first DNA rearrangement event (V–D–J recombination) involves the formation of a complete variable region (VH) gene in pre-B lymphocytes3–6. The second series of recombination events allows for a switch in heavy chain constant region class from μ to either γ3, γ1, γ2b, γ2a, ɛ or α1–3. 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 unions1–3. Tandemly repeated DNA sequences, spanning 2–5 kilobases (b), are localized 1.5 kilobase pairs 5′ of each CH gene and have been termed CH 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 CH switching by homologous DNA recombination8. Unlike other switch regions, a large portion of the Sμ region (3 kb) consists of essentially pure tandem repeats of GAGCT which are occasionally interrupted by a GGGGT8. However, the precise sites of switch-recombination in Sμ are generally located considerably 5′ of this genetically unstable stretch9,10 of GAGCT repeats (Fig. 1). We now report the properties of a novel CH S region sequence, YAGGTTG, which is 5′ of switch recombination sites and preferentially repeated in S regions.

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