Targeting of human switch recombination breakpoints: implications for the mechanism of mu-gamma isotype switching.

Abstract

We recently characterized the allelic variants of the human Sgamma4 region which makes it possible to accurately identity and map Smu-Sgamma4 fragments from in vivo switched B cells. Twenty-six fragments were identified and a comparison was made with all previously published Smu-Sgamma sequences ( n = 82). Switch recombination outside the region flanking the Sgamma repeat sequence is a rare event in vivo and differences previously observed in patterns between in vitro and in vivo switched B cells appear to be artefactual and due to constraints of the methods used. Furthermore, internal deletions in the switch regions are common, but do not appear to be involved in isotype stabilization. A slight preference for switching to the B (SNIP) site was observed, suggesting a limited importance of both the B and A (SNAP) in the switching process. Mutations can be identified on either one or both sides of the switch junction, showing involvement of an error-prone process, and the pattern of mutations/substitutions at and around the junctions shows non-random nucleotide replacements by the enzyme(s) involved which may help in its future identification.