Somatic hypermutation in the heavy chain locus correlates with transcription

Three mutant immunoglobulin heavy chain (IgH) insertion mice were generated in which a targeted nonfunctional IgH passenger transgene was either devoid of promoter (pdelta) or was placed under the transcriptional control of either its own RNA polymerase II-dependent IgH promoter (pII) or a RNA polymerase I-dependent promoter (pI). While the transgene mutation-frequency (0.85%) in memory B cells of pI mice was reduced compared to that in pII mice (1.4%), the distribution and the base exchange pattern of point mutations were comparable. In pdelta mice, the mutation frequency was drastically reduced (0.09%). The mutation frequencies correlated with the levels of transgene-specific pre-mRNA expressed in germinal center B cells isolated from the mutant mice.