ArticleProceedings of the National Academy of Sciences of the United States of America1996
Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1996. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 63 citations in OpenAlex.
- Homology Modeling-Based in Silico Affinity Maturation Improves the Affinity of a Nanobody.International journal of molecular sciences · 2019Article
- Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation.Frontiers in immunology · 2017Article
- Antibodyomics: bioinformatics technologies for understanding B-cell immunity to HIV-1.Immunological reviews · 2017Review
- Functional Versatility of AGY Serine Codons in Immunoglobulin Variable Region Genes.Frontiers in immunology · 2016Article
- AID to overcome the limitations of genomic information by introducing somatic DNA alterations.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2006Review
- Deficiency of somatic hypermutation of immunoglobulin G transcripts is a better predictor of severe respiratory tract infections than lack of memory B cells in common variable immunodeficiency.Journal of clinical immunology · 2005Article
- AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization.Proceedings of the National Academy of Sciences of the United States of America · 2002Article
- Review
- The intrinsic hypermutability of antibody heavy and light chain genes decays exponentially.The EMBO journal · 2001Article
- Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire.Leukemia · 2000Review
- A hypermutable insert in an immunoglobulin transgene contains hotspots of somatic mutation and sequences predicting highly stable structures in the RNA transcript.The Journal of experimental medicine · 1998Article
- Both DNA strands of antibody genes are hypermutation targets.Proceedings of the National Academy of Sciences of the United States of America · 1998Article
- Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease.Proceedings of the National Academy of Sciences of the United States of America · 1998Article
- The Ig mutator is dependent on the presence, position, and orientation of the large intron enhancer.Proceedings of the National Academy of Sciences of the United States of America · 1998Article
- Inherent properties of somatic hypermutation as revealed by human non-productive VH6 immunoglobulin rearrangements.Immunology · 1998Article
- Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes.The Journal of experimental medicine · 1998Article
- Cells strongly expressing Ig(kappa) transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers.The EMBO journal · 1997Article
- Sequence dependent hypermutation of the immunoglobulin heavy chain in cultured B cells.Proceedings of the National Academy of Sciences of the United States of America · 1997Article
- The antibody mining toolbox: an open source tool for the rapid analysis of antibody repertoires.mAbsArticle
Corrections and comments
- Erratum issued
Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Affinity maturation of antibodies requires localized hypermutation and antigen selection. Hypermutation is particularly active in certain regions (notably the CDRs of light and heavy chains) due to the local accumulation of hot spots. We have now analyzed the role of individual nucleotides in the origin of hot spots and show that mutability is largely defined by the nucleotide sequence. We compared the mutability profile of wild-type and modified kappa transgenes that contain silent mutations in the CDR1 segment. We found a new hot spot created at the third base of Ser-31 when its wild-type AGT codon was substituted by AGC. Two major hot spots associated with this AGC vanished when Ser-31 was encoded by the synonymous TCA. In addition to these, which were the most prominent changes, there were compensatory alterations in mutability of residues not directly related to the introduced silent mutations, so that the average hypermutation remained constant. Thus, mutations arising early in the immune response, even silent ones, could affect the mutability of critical residues and alter the pattern of affinity maturation. When analyzing hybridomas, we detected such alterations, but they seemed to better correlate with changes in average rather than local mutation rates. Overall, this paper shows how evolution could have optimized the mutability of individual residues to minimize deleterious mutations. Thus, the optimal strategy for affinity maturation may involve the incorporation of multiple point mutations before antigen selection of the relevant cells.
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