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 γ3, γ1, γ2b, γ2a, ∈ 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 recombination⁸. 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 GGGGT⁸. 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.