Recombination events near the immunoglobulin C.mu. gene join variable and constant region genes, switch heavy-chain expression, or inactivate the locus

Abstract

Ig H chain expression is initiated by recombination between a variable region (VH) gene and one of several joining region (JH) genes located near the .mu. constant region (C.mu.) gene, and the active VH gene can subsequently switch to another CH gene. The general mechanism for CH switching involves recombination between sites within the JH-C.mu. intervening sequence and the 5'' flanking region of another CH gene is supported by Southern blot hybridization analysis of 8 IgG- and IgA-secreting plasmacytomas. An alternative model requiring successive VH linkage to similar JH clusters near each CH gene is shown to be very unlikely since the mouse genome appears to contain only 1 complement of the JH locus and no JH gene was detectable within large cloned sequences flanking germline C.gamma.3 and C.gamma.1 genes. Thus, VH-JH joining and CH switching are mediated by separate regions of the joining-switch or J-S element. In each plasmacytoma examined, the J-S element had undergone recombination within both the JH locus and the switch region and was linked to the functional CH gene in an IgG3, an IgG1 and 3 IgA secretors. Both JH joining and CH switching occurred by deletion of DNA. Switch recombination occurred at more than 1 site within the J-S element in different lines, even for recombination with the same CH gene. Significantly, although H-chain expression is restricted to 1 allele (allelic exclusion), all chromosomal complements of the JH and switch regions were rearranged in each plasmacytoma. Some rearrangements were aberrant, involving, for example, deletion of all JH genes from the allele. An error-prone recombination machinery may account for allelic exclusion in many plasmacytomas.