Targeting and selection of mutations in human Vlambda rearrangements.

The impact of somatic hypermutation on the lambda light chain repertoire of individual IgM+ peripheral B cells in the absence (nonproductive rearrangements) and presence (productive rearrangements) of selective influences was analyzed. In the 27 mutated nonproductive VlambdaJlambda, rearrangements obtained from individual peripheral B cells, a significantly greater mutational frequency was observed in the complementarity-determining region (CDR) in comparison to the framework region (FR), whereas the mutational frequencies in both the CDR and FR of the 100 mutated productive VlambdaJlambda rearrangements were significantly greater. R mutations were introduced comparably in CDR and FR of nonproductive VlambdaJlambda rearrangements, but were significantly decreased in FR of productive VlambdaJlambda rearrangements. The majority of codons defined as hot spots for R mutations were within CDR in both the nonproductive and productive VlambdaJlambda rearrangements. Targeting of mutations to RGYW/WRCY motifs was observed such that 38% of all mutations in the nonproductive VlambdaJlambda rearrangements were within RGYW/WRCY motifs. Mutations in RGYW/WRCY motifs were positively selected and accounted for >50% of all mutations in the mutated productive VlambdaJlambda rearrangements. These data indicate that targeting of the mutational machinery and selection of mutations in these targeted motifs play major roles in influencing nucleotide changes in VlambdaJlambda rearrangements.