TRANS-CHROMOSOMAL RECOMBINATION WITHIN THE IG HEAVY-CHAIN SWITCH REGION IN B-LYMPHOCYTES

Somatic DNA rearrangements in B lymphocytes, including V(D)J gene rear rangements and isotype switching, generally occur in cis, i.e., intrac hromosomally, We showed previously, however, that 3 to 7% of IgA heavy chains have the VH and C alpha regions encoded in trans. To determine whether the trans-association of V-H and C alpha occurred by trans-ch romosomal recombination, by trans-splicing, or by trans-chromosomal ge ne conversion, we generated and analyzed eight IgA-secreting rabbit hy bridomas with trans associated V-H and C alpha heavy chains. By ELISA and by nucleotide sequence analysis we found that the VH and C alpha r egions were encoded by genes that were in trans in the germline, We cl oned the rearranged VDJ-C alpha gene from a fosmid library of one hybr idoma and found that the expressed VH and C alpha genes were juxtapose d. Moreover, the juxtaposed VH and CLY genes originated from different IgH alleles, From the same hybridoma, we also identified a fosmid clo ne with the other expected product of a trans-chromosomal recombinatio n. The recombination breakpoint occurred within the S mu/S alpha regio n, indicating that the trans-association of V-H and C alpha genes occu rred by trans chromosomal recombination during isotype switching. We c onclude that trans-chromosomal recombination occurs at an unexpectedly high frequency (7%) within the IgH locus of B lymphocytes in normal a nimals, which may explain the high incidence of B-cell tumors that ari se from oncogene translocation into the IgH locus.