Imprint of somatic hypermutation differs in human immunoglobulin heavy and lambda chain variable gene segments

Somatic hypermutation (SHM) introduces mutations into immunoglobulin (Ig) variable gene segments, thus diversifying the B cell repertoire prior to positive selection of high affinity variants during maturation of T cell-dependent B cell responses. Somatic hypermutation of Ig heavy chain generates predominantly single base substitutions, favoring transition rather than transversion substitutions, and tends to direct mutations to specific 4-mer target sequences with G in second and C in third position. Here we have analyzed heavily mutated, nonproductively rearranged Ig lambda chain variable gene segments from human intestinal plasma cells, controlling for germline composition of the genes and local sequence variability. We have observed significant G·C strand bias in IgVλ, and differences in some di- and trinuleotide target preferences in IgVλ compared to IgVH. There is also a significant tendency to accumulate adjacent triplet mutations in IgVλ, which is not evident in IgVH in normal circumstances. These observations suggest that some aspect of the mechanism of somatic hypermutation operates differently in human immunoglobulin heavy and lambda light chain variable gene segments. [Copyright &y& Elsevier]