title: Trends in antibody sequence changes during the somatic hypermutation process.
abstract: Probable germline gene sequences from thousands of aligned mature Ab sequences are inferred using simple computational matching to known V(D)J genes. Comparison of the germline to mature sequences in a structural region-dependent fashion allows insights into the methods that nature uses to mature Abs during the somatic hypermutation process. Four factors determine the residue type mutation patterns: biases in the germline, accessibility from single base permutations, location of mutation hotspots, and functional pressures during selection. Germline repertoires at positions that commonly contact the Ag are biased with tyrosine, serine, and tryptophan. These residue types have a high tendency to be present in mutation hotspot motifs, and their abundance is decreased during maturation by a net conversion to other types. The heavy use of tyrosines on mature Ab interfaces is thus a reflection of the germline composition rather than being due to selection during maturation. Potentially stabilizing changes such as increased proline usage and a small number of double cysteine mutations capable of forming disulfide bonds are ascribed to somatic hypermutation. Histidine is the only residue type for which usage increases in each of the interface, core, and surface regions. The net overall effect is a conversion from residue types that could provide nonspecific initial binding into a diversity of types that improve affinity and stability. Average mutation probabilities are approximately 4% for core residues, approximately 5% for surface residues, and approximately 12% for residues in common Ag-contacting positions, excepting the those coded by the D gene.
authors.affiliation: Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. louie@alumni.northwestern.edu
authors.forename: Louis A
authors.initials: LA
authors.lastname: Clark
authors.forename: Skanth
authors.initials: S
authors.lastname: Ganesan
authors.forename: Sarah
authors.initials: S
authors.lastname: Papp
authors.forename: Herman W T
authors.initials: HW
authors.lastname: van Vlijmen
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics*; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D018095:Germ-Line Mutation; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011336:Probability; D017434:Protein Structure, Tertiary / Q000235:genetics; D012694:Serine / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin; D014364:Tryptophan / Q000235:genetics; D014443:Tyrosine / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D014443:Tyrosine; D012694:Serine; D014364:Tryptophan