Intricate Targeting of Immunoglobulin Somatic Hypermutation Maximizes the Efficiency of Affinity Maturation

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2005 May 4

PMID 15867095

Citations 37

Authors

Nai-Ying Zheng

Kenneth Wilson

Matthew Jared

Patrick C Wilson

Affiliations

Soon will be listed here.

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.

Citing Articles

Cellular and Molecular Immunity to Influenza Viruses and Vaccines.

Kasten-Jolly J, Lawrence D Vaccines (Basel). 2024; 12(4).

PMID: 38675771 PMC: 11154265. DOI: 10.3390/vaccines12040389.

Efficient evolution of human antibodies from general protein language models.

Hie B, Shanker V, Xu D, Bruun T, Weidenbacher P, Tang S Nat Biotechnol. 2023; 42(2):275-283.

PMID: 37095349 PMC: 10869273. DOI: 10.1038/s41587-023-01763-2.

Different B cell subpopulations show distinct patterns in their IgH repertoire metrics.

Ghraichy M, von Niederhausern V, Kovaltsuk A, Galson J, Deane C, Truck J Elife. 2021; 10.

PMID: 34661527 PMC: 8560093. DOI: 10.7554/eLife.73111.

Avidity optimization of a MAGE-A1-specific TCR with somatic hypermutation.

Bassan D, Gozlan Y, Sharbi-Yunger A, Tzehoval E, Greenstein E, Bitan L Eur J Immunol. 2021; 51(6):1505-1518.

PMID: 33835499 PMC: 8252751. DOI: 10.1002/eji.202049007.

Inferred Allelic Variants of Immunoglobulin Receptor Genes: A System for Their Evaluation, Documentation, and Naming.

Ohlin M, Scheepers C, Corcoran M, Lees W, Busse C, Bagnara D Front Immunol. 2019; 10:435.

PMID: 30936866 PMC: 6431624. DOI: 10.3389/fimmu.2019.00435.

References

Oprea M, Kepler T . Genetic plasticity of V genes under somatic hypermutation: statistical analyses using a new resampling-based methodology. Genome Res. 1999; 9(12):1294-304. PMC: 310983. DOI: 10.1101/gr.9.12.1294. View

Peters A, STORB U . Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. Immunity. 1996; 4(1):57-65. DOI: 10.1016/s1074-7613(00)80298-8. View

Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000; 102(5):553-63. DOI: 10.1016/s0092-8674(00)00078-7. View

Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O . Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000; 102(5):565-75. DOI: 10.1016/s0092-8674(00)00079-9. View

Zan H, Komori A, Li Z, Cerutti A, Schaffer A, Flajnik M . The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. Immunity. 2001; 14(5):643-53. PMC: 4632985. DOI: 10.1016/s1074-7613(01)00142-x. View

Rogozin I, Pavlov Y, Bebenek K, Matsuda T, Kunkel T . Somatic mutation hotspots correlate with DNA polymerase eta error spectrum. Nat Immunol. 2001; 2(6):530-6. DOI: 10.1038/88732. View

Zeng X, Winter D, Kasmer C, Kraemer K, Lehmann A, Gearhart P . DNA polymerase eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes. Nat Immunol. 2001; 2(6):537-41. DOI: 10.1038/88740. View

Diaz M, Verkoczy L, Flajnik M, Klinman N . Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase zeta. J Immunol. 2001; 167(1):327-35. DOI: 10.4049/jimmunol.167.1.327. View

Yu K, Taghva A, Lieber M . The cleavage efficiency of the human immunoglobulin heavy chain VH elements by the RAG complex: implications for the immune repertoire. J Biol Chem. 2001; 277(7):5040-6. DOI: 10.1074/jbc.M109772200. View

10.

Petersen-Mahrt S, Harris R, Neuberger M . AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature. 2002; 418(6893):99-103. DOI: 10.1038/nature00862. View

11.

Pavlov Y, Rogozin I, Galkin A, Aksenova A, Hanaoka F, Rada C . Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase eta during copying of a mouse immunoglobulin kappa light chain transgene. Proc Natl Acad Sci U S A. 2002; 99(15):9954-9. PMC: 126606. DOI: 10.1073/pnas.152126799. View

12.

Yavuz S, Yavuz A, Kraemer K, Lipsky P . The role of polymerase eta in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant. J Immunol. 2002; 169(7):3825-30. DOI: 10.4049/jimmunol.169.7.3825. View

13.

Faili A, Aoufouchi S, Flatter E, Gueranger Q, Reynaud C, Weill J . Induction of somatic hypermutation in immunoglobulin genes is dependent on DNA polymerase iota. Nature. 2002; 419(6910):944-7. DOI: 10.1038/nature01117. View

14.

Shapiro G, Wysocki L . DNA target motifs of somatic mutagenesis in antibody genes. Crit Rev Immunol. 2002; 22(3):183-200. View

15.

Lefranc M . IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. 2003; 31(1):307-10. PMC: 165532. DOI: 10.1093/nar/gkg085. View

16.

Kunkel T, Pavlov Y, Bebenek K . Functions of human DNA polymerases eta, kappa and iota suggested by their properties, including fidelity with undamaged DNA templates. DNA Repair (Amst). 2003; 2(2):135-49. DOI: 10.1016/s1568-7864(02)00224-0. View

17.

Bransteitter R, Pham P, Scharff M, Goodman M . Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc Natl Acad Sci U S A. 2003; 100(7):4102-7. PMC: 153055. DOI: 10.1073/pnas.0730835100. View

18.

Chaudhuri J, Tian M, Khuong C, Chua K, Pinaud E, Alt F . Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature. 2003; 422(6933):726-30. DOI: 10.1038/nature01574. View

19.

Ramiro A, Stavropoulos P, Jankovic M, Nussenzweig M . Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat Immunol. 2003; 4(5):452-6. DOI: 10.1038/ni920. View

20.

Dickerson S, Market E, Besmer E, Papavasiliou F . AID mediates hypermutation by deaminating single stranded DNA. J Exp Med. 2003; 197(10):1291-6. PMC: 2193777. DOI: 10.1084/jem.20030481. View