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 IgV(lambda), and differences in some di- and trinuleotide target preferences in IgV(lambda) compared to IgV(H). There is also a significant tendency to accumulate adjacent triplet mutations in IgV(lambda), which is not evident in IgV(H) 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.
Department of Histopathology, Guy's, King's and St Thomas' Medical School, St Thomas' Campus, Lambeth Palace Road, London, SE1 7EH, UK. jo.spencer@kcl.ac.uk
Laurent
L
Boursier
Wen
W
Su
Jo
J
Spencer
D000368:Aged; D003596:Cytosine / Q000032:analysis; D004247:DNA / Q000737:chemistry; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D005803:Genes, Immunoglobulin; D018392:Genomic Imprinting; D006147:Guanine / Q000032:analysis; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D007422:Intestines / Q000276:immunology; D008297:Male; D017354:Point Mutation; D027041:Somatic Hypermutation, Immunoglobulin
D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains; D006147:Guanine; D003596:Cytosine; D004247:DNA