Evolution of Ig DNA Sequence to Target Specific Base Positions Within Codons for Somatic Hypermutation

Shapiro, Gary S.; Aviszus, Katja; Murphy, James R.; Wysocki, Lawrence J.

doi:10.4049/jimmunol.168.5.2302

Cited by 54 publications

(59 citation statements)

References 38 publications

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“…A calculation of the mutability index (27), which is defined as the observed frequency that each trinucleotide motif (XYC) is deaminated compared with the expected frequency with no sequence bias, provides quantitative comparison of mutant and WT AID deamination specificities (5,21). We have determined the MI values in the 16 trinucleotide motifs for WT AID and four of the point mutants, L98R, R174S, F15L, and S43P (Table 2).…”

Section: Resultsmentioning

confidence: 99%

A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

Prochnow

Pham

et al. 2012

Journal of Biological Chemistry

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Background: HIGM-2 syndrome results from mutations spanning AID. Results: AID mutations are characterized biochemically and analyzed using a surrogate Apo3G structure. Conclusion: Catalytically active mutants retain salient enzymatic properties of WT AID; catalytically inactive mutants retain salient ssDNA binding properties of WT AID. Significance: We identify four structural classes of mutants and discuss the catalytic consequences of each mutation.

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Section: Resultsmentioning

confidence: 99%

A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

Prochnow

Pham

et al. 2012

Journal of Biological Chemistry

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“…This evolutionary process is reflected in the fact that codons used in the CDRs are more likely to create AID hotspots and to result in replacement mutations than the codons used in the frameworks (FWs) (7,32,33). There is the potential for an even more intricate process (32), as hotspots for AID can assume a variety of sequences, each undergoing mutations at different frequencies (6,7,34). Particularly interesting is the WGCW motif, which provides two overlapping WRC motifs on opposing strands of the DNA (3,5,7).…”

Section: Significancementioning

confidence: 99%

Overlapping hotspots in CDRs are critical sites for V region diversification

Wei

Chahwan

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.A fter an encounter with antigen and subsequent migration into the germinal centers of the secondary lymphoid organs, B cells undergo a regulated cascade of mutational events that occur at a very high frequency and are largely restricted to the variable (V) and switch (S) regions of the Ig heavy chain locus and the V region of the light chain locus. These mutagenic events are responsible for the somatic hypermutation (SHM) of the V regions and the class switch recombination of the constant (C) regions that are required for protective antibodies (1, 2). Both SHM and class switch recombination are initiated by activationinduced deaminase (AID) that preferentially deaminates the dC residues in WRC (W = A/T, R = A/G) hotspot motifs at frequencies 2-10-fold higher than SYC (S = G/C; Y = C/T) cold spots (3-7). During V region SHM, the resulting dU:G mismatch can then be replicated during S-phase to produce transition mutations, be processed by uracil-DNA glycosylase 2 and apurinic/ apyrimidinic endonucleases through the base excision repair pathway to produce both transitions and transversions (8-10), or be recognized by MutS homolog (MSH)2/MSH6 of the mismatch repair (MMR) complex that recruits the low-fidelity polymerase eta (Polη) to generate additional mutations at neighboring A:T residues (11).The specificity of AID targeting to the Ig gene has been under intense investigation. Studies have shown that AID deamination and mutagenesis targets single-stranded DNA substrates generated during ...

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“…In addition, the position-independent trinucleotide mutability indexes (shown as "combined" in Table V) was determined. These indexes were compared with the trinucleotide mutability indexes derived by Shapiro et al (11,43) for human V H mutations (Table V). These comparisons indicate several important points.…”

Section: Sequence-specific Patterns Of Somatic Mutationmentioning

confidence: 99%

The Nucleotide Targets of Somatic Mutation and the Role of Selection in Immunoglobulin Heavy Chains of a Teleost Fish

Yang

Waldbieser

Lobb

2006

The Journal of Immunology

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Sequence analysis of H chain cDNA derived from the spleen of an individual catfish has shown that somatic mutation occurs within both the VH- and JH-encoded regions. Somatic mutation preferentially targets G and C nucleotides with approximately balanced frequencies, resulting in the predominant accumulation of G-to-A and C-to-T substitutions that parallel the activation-induced cytidine deaminase nucleotide exchanges known in mammals. The overall mutation rate of A nucleotides is not significantly different from that expected by sequence-insensitive mutations, and a significant bias exists against mutations occurring in T. Targeting of mutations is dependent upon the sequence of neighboring nucleotides, allowing statistically significant hotspot motifs to be identified. Dinucleotide, trinucleotide, and RGYW analyses showed that mutational targets in catfish are restricted when compared with the spectrum of targets known in mammals. The preferential targets for G and C mutation are the central GC positions in both AGCT and AGCA. The WA motif, recognized as a mammalian hotspot for A mutations, was not a significant target for catfish mutations. The only significant target for A mutations was the terminal position in AGCA. Lastly, comparisons of mutations located in framework region and CDR codons coupled with multinomial distribution studies found no substantial evidence in either independent or clonally related VDJ rearrangements to indicate that somatic mutation coevolved with mechanisms that select B cells based upon nonsynonymous mutations within CDR-encoded regions. These results suggest that the principal role of somatic mutation early in phylogeny was to diversify the repertoire by targeting hotspot motifs preferentially located within CDR-encoded regions.

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Evolution of Ig DNA Sequence to Target Specific Base Positions Within Codons for Somatic Hypermutation

Cited by 54 publications

References 38 publications

A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

A Structural Basis for the Biochemical Behavior of Activation-induced Deoxycytidine Deaminase Class-switch Recombination-defective Hyper-IgM-2 Mutants

Overlapping hotspots in CDRs are critical sites for V region diversification

The Nucleotide Targets of Somatic Mutation and the Role of Selection in Immunoglobulin Heavy Chains of a Teleost Fish

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