title: Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation.
abstract: It is believed that immunoglobulin-variable region gene (IgV) somatic hypermutation (SHM) is initiated by activation-induced cytidine deaminase (AID) upon deamination of cytidine to deoxyuracil. Patch-excision repair of these lesions involving error prone DNA polymerases such as poleta causes mutations at all base positions. If not repaired, the deaminated nucleotides on the coding and noncoding strands result in C-to-T and G-to-A exchanges, respectively. Herein it is reported that IgV gene evolution has been considerably influenced by the need to accommodate extensive C deaminations and the resulting accumulation of C-to-T and G-to-A exchanges. Although seemingly counterintuitive, the precise placement of C and G nucleotides causes most C-to-T and G-to-A mutations to be silent or conservative. We hypothesize that without intricate positioning of C and G nucleotides the efficiency of affinity maturation would be significantly reduced due to a dominance of replacements caused by C and G transition mutations. The complexity of these evolved biases in codon use are compounded by the precise concomitant hotspot/coldspot targeting of AID activity and Poleta errors to maximize SHM in the CDRs and minimize mutations in the FWRs.
authors.affiliation: Molecular Immunogenetics Program, The Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Zheng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wilson
authors.forename: Matthew
authors.initials: M
authors.lastname: Jared
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D003062:Codon / Q000235:genetics*; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D019143:Evolution, Molecular; D005434:Flow Cytometry; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099270:Y-Family DNA Polymerases
chemical_list: D003062:Codon; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase; D004259:DNA-Directed DNA Polymerase; D007135:Immunoglobulin Variable Region; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases