ArticleProceedings of the National Academy of Sciences of the United States of America2015
Overlapping hotspots in CDRs are critical sites for V region diversification.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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49 citing papers in PubMed, 71 citations in OpenAlex.
- Article
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- Human naïve B cells show evidence of anergy and clonal redemption following vaccination.NPJ vaccines · 2025Article
- Modular cytosine base editing promotes epigenomic and genomic modifications.Nucleic acids research · 2024Article
- Interpretable deep learning reveals the role of an E-box motif in suppressing somatic hypermutation of AGCT motifs within human immunoglobulin variable regions.Frontiers in immunology · 2024Article
- Mechanism and regulation of secondary immunoglobulin diversification.Cell cycle (Georgetown, Tex.) · 2023Review
- Germline-encoded specificities and the predictability of the B cell response.PLoS pathogens · 2023Article
- Article
- Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe.Frontiers in immunology · 2023Review
- Diversification of immunoglobulin genes by gene conversion in the domestic chicken (Discovery immunology · 2023Article
- Ancestral reconstruction reveals catalytic inactivation of activation-induced cytidine deaminase concomitant with cold water adaption in the Gadiformes bony fish.BMC biology · 2022Article
- Immunoglobulin somatic hypermutation in a defined biochemical system recapitulates affinity maturation and permits antibody optimization.Nucleic acids research · 2022Article
- The mechanisms of human lymphoid chromosomal translocations and their medical relevance.Critical reviews in biochemistry and molecular biology · 2022Article
- Deep learning model of somatic hypermutation reveals importance of sequence context beyond hotspot targeting.iScience · 2022Article
- Chickens, more than humans, focus the diversity of their immunoglobulin genes on the complementarity-determining region but utilise amino acids, indicative of a more cross-reactive antibody repertoire.Frontiers in immunology · 2022Article
- Rapid generation of potent antibodies by autonomous hypermutation in yeast.Nature chemical biology · 2021Article
- A Bayesian model based computational analysis of the relationship between bisulfite accessible single-stranded DNA in chromatin and somatic hypermutation of immunoglobulin genes.PLoS computational biology · 2021Article
- Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Activation-induced deaminase (AID) mediates the somatic hypermutation (SHM) of Ig variable (V) regions that is required for the affinity maturation of the antibody response. An intensive analysis of a published database of somatic hypermutations that arose in the IGHV3-23*01 human V region expressed in vivo by human memory B cells revealed that the focus of mutations in complementary determining region (CDR)1 and CDR2 coincided with a combination of overlapping AGCT hotspots, the absence of AID cold spots, and an abundance of polymerase eta hotspots. If the overlapping hotspots in the CDR1 or CDR2 did not undergo mutation, the frequency of mutations throughout the V region was reduced. To model this result, we examined the mutation of the human IGHV3-23*01 biochemically and in the endogenous heavy chain locus of Ramos B cells. Deep sequencing revealed that IGHV3-23*01 in Ramos cells accumulates AID-induced mutations primarily in the AGCT in CDR2, which was also the most frequent site of mutation in vivo. Replacing the overlapping hotspots in CDR1 and CDR2 with neutral or cold motifs resulted in a reduction in mutations within the modified motifs and, to some degree, throughout the V region. In addition, some of the overlapping hotspots in the CDRs were at sites in which replacement mutations could change the structure of the CDR loops. Our analysis suggests that the local sequence environment of the V region, and especially of the CDR1 and CDR2, is highly evolved to recruit mutations to key residues in the CDRs of the IgV region.
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