Analysis of somatic mutations in kappa transgenes.

Hackett, Jr J; Rogerson, Brian J.; O’Brien, Rebecca L.; Storb, Ursula

doi:10.1084/jem.172.1.131

Cited by 47 publications

(40 citation statements)

References 27 publications

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“…When such a rearrangement involves the Ig recombination recognition sequence in the intron between J O and C O , the nonproductive rearrangement might be retained on the chromosome, but removed from the intronic enhancer. As proximity to the intronic enhancer is thought to be necessary for somatic hypermutation [4,[13][14][15], the inclusion of these nonproductive rearrangements in the analysis might contribute to the apparent lower mutational frequency of nonproductively rearranged V O J O genes. There are several reasons that this is an unlikely explanation for the current results.…”

Section: Discussionmentioning

confidence: 98%

Targeting and subsequent selection of somatic hypermutations in the human Vκ repertoire

1999

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The number and distribution of nucleotide substitutions in human VκJκ genes were examined using a PCR technique that analyzed nonproductive and productive rearrangements amplified from genomic DNA of individual B cells. The results indicate that the mutational mechanism introduces replacement (R) mutations comparably throughout the length of the VκJκ rearrangement, but tends to target specific triplets. Moreover, hotspots of mutational activity were identified in complementarity determining regions (CDR). A marked increase in the frequency of R mutations in CDR was noted when productive were compared to nonproductive rearrangements, indicating that these were selected into the expressed repertoire. Of note, amino acids encoded by codons adjacent to hotspots of mutation were also positively selected implying that similar regions were targeted for hypermutation and subsequent selection. In contrast to the distribution of CDR mutations, R mutations in the framework (FR) regions tended to be eliminated from productive VκJκ rearrangements, implying that the somatic hypermutational machinery frequently introduced amino acid changes that were deleterious to the structural integrity of the κ chain protein. The difference in the ratio of R to silent mutations in CDR and FR in the expressed repertoire, therefore, reflects the summation of positive selection of R mutations in the CDR and the elimination of R mutations in the FR. The data indicate that the balance between targeted mutation of VκJκ rearrangements and subsequent selection and elimination governs the pattern of mutations manifest within the expressed κ repertoire.

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Section: Discussionmentioning

confidence: 98%

Targeting and subsequent selection of somatic hypermutations in the human Vκ repertoire

1999

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“…For example, the expression levels of transgenes strongly correlate with the levels of mutation (5)(6)(7). In addition, hypermutation of the Ig genes begins just downstream of the promoter (8,9) and ends well before the C region (10). This ϳ2-kb window from the promoter for SHM is observed regardless of which J gene segment is rearranged (8,11).…”

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confidence: 95%

Roles of the Ig κ Light Chain Intronic and 3′ Enhancers inIgkSomatic Hypermutation

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Gao

Odegard

et al. 2006

The Journal of Immunology

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Somatic hypermutation (SHM) of the rearranged Ig genes is required for the affinity maturation of Abs. SHM is almost exclusively targeted to the rearranged Ig loci, but the mechanism of this gene-specific targeting remains unclear. The Ig κ L chain locus contains multiple enhancers, including the MAR/intronic (iEκ) and 3′ enhancers (3′Eκ). Previous transgenic studies indicate that both κ enhancers are individually necessary for SHM of Igk. In contrast, later studies of Ag-selected Vκ genes in 3′Eκ−/− mice found no absolute requirement for 3′Eκ in κ SHM. To address the roles of the two κ enhancers in SHM in a physiological context, we analyzed SHM of the endogenous Igk in mice with a targeted deletion of either iEκ or 3′Eκ in Peyer’s patch germinal center B cells. Our findings indicate that, although 3′Eκ is quantitatively important for SHM of Igk, iEκ is not required for κ SHM. In addition, a reduction of κ mRNA levels is also detected in activated 3′Eκ−/− B cells. These findings suggest that iEκ and 3′Eκ play distinct roles in regulating Igk transcription and SHM.

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“…Because SHM is normally detected close to the TSS (13,14), biotin linker-enriched DNA fragments were analyzed by a promoter array to identify unknown AID targets. Table S1 lists the genes whose signals increased after 3 h of 4-OHT treatment, compared with untreated samples with false discovery rate (FDR) values <0.3.…”

Section: Aid Targets Identified By Promoter Array and Whole Genomementioning

confidence: 99%

“…Indeed, AID-induced mutations (SHM) are generally detected in a region within 2 kb downstream of the transcription start site (TSS) (13,14). Transcription appears to play two roles in the targeting of cleavage sites.…”

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confidence: 99%

Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes

Kato¹,

Begum²,

Burroughs

et al. 2012

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

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Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and class-switch recombination in activated B cells. AID is also known to target nonimmunoglobulin genes and introduce mutations or chromosomal translocations, eventually causing tumors. To identify as-yet-unknown AID targets, we screened early AID-induced DNA breaks by using two independent genome-wide approaches. Along with known AID targets, this screen identified a set of unique genes (SNHG3, MALAT1, BCL7A, and CUX1) and confirmed that these loci accumulated mutations as frequently as Ig locus after AID activation. Moreover, these genes share three important characteristics with the Ig gene: translocations in tumors, repetitive sequences, and the epigenetic modification of chromatin by H3K4 trimethylation in the vicinity of cleavage sites.deep sequencing | end labeling by biotin oligonucleotide | microarray

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Analysis of somatic mutations in kappa transgenes.

Cited by 47 publications

References 27 publications

Targeting and subsequent selection of somatic hypermutations in the human Vκ repertoire

Targeting and subsequent selection of somatic hypermutations in the human Vκ repertoire

Roles of the Ig κ Light Chain Intronic and 3′ Enhancers inIgkSomatic Hypermutation

Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes

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