The intrinsic hypermutability of antibody heavy and light chain genes decays exponentially.
Somatic hypermutation, essential for the affinity maturation of antibodies, is restricted to a small segment of DNA. The upstream boundary is sharp and is probably related to transcription initiation. However, for reasons unknown, the hypermutation domain does not encompass the whole transcription unit, notably the C-region exon. Since analysis of the downstream decay of hypermutation is obscured by sequence-dependent hot and cold spots, we describe a strategy to minimize these fluctuations by computing mutations of different sequences located at similar distances from the promoter. We pool large databases of mutated heavy and light chains and analyse the decay of mutation frequencies. We define an intrinsic decay of probability of mutation that is remarkably similar for heavy and light chains, faster than anticipated and consistent with an exponential fit. Indeed, quite apart from hot spots, the intrinsic probability of mutation at CDR1 can be almost twice that of CDR3. The analysis has mechanistic implications for current and future models of hypermutation.
Rada
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MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. car@mrc-lmb.cam.ac.uk
Milstein
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D000818:Animals; D001665:Binding Sites; D005803:Genes, Immunoglobulin; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016296:Mutagenesis; D011401:Promoter Regions, Genetic
D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains