Gene conversion in human rearranged immunoglobulin genes

Darlow, John M; Stott, David I.

doi:10.1007/s00251-006-0113-6

Cited by 20 publications

(19 citation statements)

References 38 publications

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“…Further, several of these upstream donor genes are functional, whereas in chickens there exists a single functional germline VH and a pool of upstream pseudogenes that are used exclusively as donor genes for gene conversion. Interestingly, and consistent with earlier data [47], we report a detectable amount of gene conversion in the human IgG repertoire, but not in the mouse. The gene conversion tract lengths are significantly lower in the expressed human IgG repertoire as compared to the rabbit and chicken, but nonetheless are of high statistical confidence (p<0.05).…”

Section: Discussionsupporting

confidence: 93%

“…In rabbits, 23% of IgG sequences and 32% of Igκ sequences were the products of gene conversion. There have been previous, although somewhat controversial, indications suggesting gene conversion occurs in humans and mice as well, albeit at a much lower frequency [47], [48], [49]. We find that, in the mouse, putative gene conversion events are nearly absent, with an estimated frequency of 0.1% of all unique IgG sequences.…”

Section: Resultscontrasting

confidence: 43%

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Systematic Characterization and Comparative Analysis of the Rabbit Immunoglobulin Repertoire

et al. 2014

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Rabbits have been used extensively as a model system for the elucidation of the mechanism of immunoglobulin diversification and for the production of antibodies. We employed Next Generation Sequencing to analyze Ig germline V and J gene usage, CDR3 length and amino acid composition, and gene conversion frequencies within the functional (transcribed) IgG repertoire of the New Zealand white rabbit (Oryctolagus cuniculus). Several previously unannotated rabbit heavy chain variable (VH) and light chain variable (VL) germline elements were deduced bioinformatically using multidimensional scaling and k-means clustering methods. We estimated the gene conversion frequency in the rabbit at 23% of IgG sequences with a mean gene conversion tract length of 59±36 bp. Sequencing and gene conversion analysis of the chicken, human, and mouse repertoires revealed that gene conversion occurs much more extensively in the chicken (frequency 70%, tract length 79±57 bp), was observed to a small, yet statistically significant extent in humans, but was virtually absent in mice.

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Section: Discussionsupporting

confidence: 93%

Section: Resultscontrasting

confidence: 43%

Systematic Characterization and Comparative Analysis of the Rabbit Immunoglobulin Repertoire

et al. 2014

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“…The high concentration of somatic mutations in these few RGYW motifs indicated that the motifs likely targeted by AID is restricted in the catfish compared with that known in mammals. These results allowed the alternative hypothesis that hybrid formation was mediated by AID to be pursued (12, 27–28, 31). If revision occurred via an initiating AID-induced DNA lesion, the targeted site would be expected to be within the junctional boundary where the recipient and donor shared the same sequence.…”

Section: Resultsmentioning

confidence: 87%

“…As suggested by earlier studies, if the heptamers in both the donor cRSS and the recipient cRSS are in the same orientation and the same relative coding region locations, then a RAG-mediated recombination event that results in a hybrid joint could yield a functional and apparently seamless revision product (26–28). Alternatively, it has been postulated that receptor revision might result from an AID-dependent, gene conversion type event (12, 27, 28, 31). The mechanisms, the frequency, and the location where revisions may occur present major challenges in understanding the potential biological significance of receptor revision in B cell populations.…”

Section: Introductionmentioning

confidence: 99%

Patterns of Receptor Revision in the Immunoglobulin Heavy Chains of a Teleost Fish

Lange

Waldbieser²,

Lobb

2009

The Journal of Immunology

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H chain cDNA libraries were constructed from the RNA derived from seven different organs and tissues from the same individual catfish. Sequence analysis of >300 randomly selected clones identified clonal set members within the same or different tissues, and some of these represented mosaic or hybrid sequences. These hybrids expressed VH members of the same or different VH families within different regions of the same clone. Within some clonal sets multiple hybrids were identified, and some of these represented the products of sequential VH replacement events. Different experimental methods confirmed that hybrid clones identified in the cDNA library from one tissue could be reisolated in the cDNA pool or from the total RNA derived from the same or a different tissue, indicating that these hybrids likely represented the products of in vivo receptor revision events. Murine statistical recombination models were used to evaluate cryptic recombination signal sequences (cRSS), and significant cRSS pairs in the predicted VH donor and recipient were identified. These models supported the hypothesis that seamless revisions may have occurred via hybrid joint formation. The heptamers of the cRSS pairs were located at different locations within the coding region, and different events resulted in the replacement of one or both CDR as well as events that replaced the upstream untranslated region and the leader region. These studies provide phylogenetic evidence that receptor revision may occur in clonally expanded B cell lineages, which supports the hypothesis that additional levels of somatic H chain diversification may exist.

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“…Indeed, gene conversion machinery commonly appears active across cell types or species, as a DSB can induce homology-directed repair in an I-SceI site-containing reporter gene in different cells. Nevertheless, AID-induced lesions rarely cause immunoglobulin gene conversion in human B cells, despite the presence of multiple pseudo-V genes in humans (46). Although it remains uncertain whether an Ig gene conversion-specific enzyme that acts downstream of AID or DSB exists, such an enzyme might contribute to the DSB-induced gene conversion.…”

Section: Discussionmentioning

confidence: 99%

A double-strand break can trigger immunoglobulin gene conversion

Bastianello

Arima

2016

Nucleic Acids Res

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All three B cell-specific activities of the immunoglobulin (Ig) gene re-modeling system—gene conversion, somatic hypermutation and class switch recombination—require activation-induced deaminase (AID). AID-induced DNA lesions must be further processed and dissected into different DNA recombination pathways. In order to characterize potential intermediates for Ig gene conversion, we inserted an I-SceI recognition site into the complementarity determining region 1 (CDR1) of the Ig light chain locus of the AID knockout DT40 cell line, and conditionally expressed I-SceI endonuclease. Here, we show that a double-strand break (DSB) in CDR1 is sufficient to trigger Ig gene conversion in the absence of AID. The pattern and pseudogene usage of DSB-induced gene conversion were comparable to those of AID-induced gene conversion; surprisingly, sometimes a single DSB induced multiple gene conversion events. These constitute direct evidence that a DSB in the V region can be an intermediate for gene conversion. The fate of the DNA lesion downstream of a DSB had more flexibility than that of AID, suggesting two alternative models: (i) DSBs during the physiological gene conversion are in the minority compared to single-strand breaks (SSBs), which are frequently generated following DNA deamination, or (ii) the physiological gene conversion is mediated by a tightly regulated DSB that is locally protected from non-homologous end joining (NHEJ) or other non-homologous DNA recombination machineries.

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Gene conversion in human rearranged immunoglobulin genes

Cited by 20 publications

References 38 publications

Systematic Characterization and Comparative Analysis of the Rabbit Immunoglobulin Repertoire

Systematic Characterization and Comparative Analysis of the Rabbit Immunoglobulin Repertoire

Patterns of Receptor Revision in the Immunoglobulin Heavy Chains of a Teleost Fish

A double-strand break can trigger immunoglobulin gene conversion

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