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Tasuku Honjo - One of the best experts on this subject based on the ideXlab platform.
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accelerated systemic autoimmunity in the absence of Somatic Hypermutation in 564igi a mouse model of systemic lupus with knocked in heavy and light chain genes
Frontiers in Immunology, 2017Co-Authors: Gabrielle Mcdonald, Tasuku Honjo, Reiko Shinkura, Erik Selsing, Carlos Medina, Monika Pilichowska, John F Kearney, Henry H Wortis, Thereza ImanishikariAbstract:564Igi mice have knocked-in Ig heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for Somatic Hypermutation (SHM) and class switch recombination (CSR). To determine the role of each of these functions in the generation of pathogenic autoantibodies we generated 564Igi mice that carry a mutant AID-encoding gene, Aicda (AicdaG23S), which is capable of promoting CSR but not SHM. We found that 564Igi AicdaG23S mice secreted class-switched antibodies at levels approximately equal to 564Igi mice. However, compared to 564Igi mice, 564Igi AicdaG23S mice had increased pathogenic IgG antibodies and severe SLE-like disease, including, glomerulonephritis, and early death. We suggest that in 564Igi mice SHM by AID changes Ig receptors away from self-reactivity, thereby mitigating the production of autoantibody, providing a novel mechanism of tolerance.
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accumulation of the fact complex as well as histone h3 3 serves as a target marker for Somatic Hypermutation
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Masatoshi Aida, Nasim A Begum, Nesreen Hamad, Andre Stanlie, Tasuku HonjoAbstract:Somatic Hypermutation (SHM) requires not only the expression of activation-induced cytidine deaminase, but also transcription in the target regions. However, how transcription guides activation-induced cytidine deaminase in targeting SHM to the Ig genes is not fully understood. Here, we found that the “facilitates chromatin transcription” (FACT) complex promotes SHM by RNAi screening of transcription elongation factors. Furthermore, FACT and histone H3.3, a hallmark of transcription-coupled histone turnover, are enriched at the V(D)J region, 5′ flanking sequence of the Sμ switch region and the light chain Jκ 5 segment region in the Ig loci. The regions with the most abundant deposition of FACT and H3.3 were also the most efficient targets of SHM. These results demonstrate the importance of histone-exchanging dynamics at the chromatin of SHM targets, especially in Ig genes.
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decrease in topoisomerase i is responsible for activation induced cytidine deaminase aid dependent Somatic Hypermutation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Maki Kobayashi, Yoko Kitawaki, Zahra Sabouri, Somayeh Sabouri, Takaya Abe, Hiroshi Kiyonari, Tasuku HonjoAbstract:Somatic Hypermutation (SHM) and class-switch recombination (CSR) of the Ig gene require both the transcription of the locus and the expression of activation-induced cytidine deaminase (AID). During CSR, AID decreases the amount of topoisomerase I (Top1); this decrease alters the DNA structure and induces cleavage in the S region. Similarly, Top1 is involved in transcription-associated mutation at dinucleotide repeats in yeast and in triplet-repeat contraction in mammals. Here, we report that the AID-induced decrease in Top1 is critical for SHM. Top1 knockdown or haploinsufficiency enhanced SHM, whereas Top1 overexpression down-regulated it. A specific Top1 inhibitor, camptothecin, suppressed SHM, indicating that Top1's activity is required for DNA cleavage. Nonetheless, suppression of transcription abolished SHM, even in cells with Top1 knockdown, suggesting that transcription is critical. These results are consistent with a model proposed for CSR and triplet instability, in which transcription-induced non-B structure formation is enhanced by Top1 reduction and provides the target for irreversible cleavage by Top1. We speculate that the mechanism for transcription-coupled genome instability was adopted to generate immune diversity when AID evolved.
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mice carrying a knock in mutation of aicda resulting in a defect in Somatic Hypermutation have impaired gut homeostasis and compromised mucosal defense
Nature Immunology, 2011Co-Authors: Reiko Shinkura, Min Wei, Yasuko Doi, Mikako Maruya, Sidonia Fagarasan, Tasuku HonjoAbstract:Secretory IgA protects mucosal surfaces. Honjo and colleagues show that Somatic Hypermutation of IgA dependent on the cytidine deaminase AID is necessary to maintain gut immune homeostasis and shapes the intestinal microflora population.
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apex2 is required for efficient Somatic Hypermutation but not for class switch recombination of immunoglobulin genes
International Immunology, 2009Co-Authors: Zahra Sabouri, Nasim A Begum, Ilmi Okazaki, Reiko Shinkura, Hitoshi Nagaoka, Daisuke Tsuchimoto, Yusaku Nakabeppu, Tasuku HonjoAbstract:The DNA cleavage step in both the class switch recombination (CSR) and Somatic Hypermutation (SHM) of Ig genes is initiated by activation-induced cytidine deaminase (AID). However, the detailed mechanisms of the DNA strand cleavage in SHM and CSR are still largely unknown. Recently, the apurinic/apyrimidinic endonucleases, Apex1 and Apex2, were reported to be involved in the DNA cleavage step of CSR. Here, we examined the role of Apex2 in SHM using Apex2-deficient mice and found that the Apex2 deficiency caused a drastic reduction in the frequency of SHM and the number of mutations per mutated clone without affecting the pattern of base substitution. These results suggest that Apex2 may play a critical role in SHM through its 3'-5' exonuclease activity. Unexpectedly, the efficiency of CSR was not reduced in Apex2-deficient B cells. In addition, Apex1 knockdown in CH12F3-2 B lymphoma cells did not affect the CSR frequency, suggesting that neither Apex1 nor Apex2 plays a major role in CSR.
Sumaira Bilal - One of the best experts on this subject based on the ideXlab platform.
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t cell receptor alpha chain genes in the teleost ballan wrasse labrus bergylta are subjected to Somatic Hypermutation
Frontiers in Immunology, 2018Co-Authors: Sumaira Bilal, Kai Kristoffer Lie, Øystein Sæle, Ivar HordvikAbstract:Previously, Somatic Hypermutation (SHM) was considered to be exclusively associated with affinity maturation of antibodies, although it also occurred in T cells under certain conditions. More recently, it has been shown that SHM generates diversity in the variable domain of T cell receptor (TCR) in camel and shark. Here, we report Somatic mutations in TCR alpha chain genes of the teleost fish, Ballan wrasse (Labrus bergylta), and show that this mechanism adds extra diversity to the polymorphic constant (C) region as well. The organization of the TCR alpha/delta locus in Ballan wrasse was obtained from a scaffold covering a single copy C alpha gene, 65 putative J alpha segments, a single copy C delta gene, 1 J delta segment, and 2 D delta segments. Analysis of 37 fish revealed 6 allotypes of the C alpha gene, each with 1-3 replacement substitutions. Somatic mutations were analyzed by molecular cloning of TCR alpha chain cDNA. Initially, 79 unique clones comprising four families of variable (V) alpha genes were characterized. Subsequently, a more restricted PCR was performed to focus on a specific V gene. Comparison of 48 clones indicated that the frequency of Somatic mutations in the VJ region was 4.5/1,000 base pairs (bps), and most prevalent in complementary determining region 2 (CDR2). In total, 45 different J segments were identified among the 127 cDNA clones, counting for most of the CDR3 diversity. The number of mutations in the C alpha chain gene was 1.76 mutations/1,000 bps and A nucleotides were most frequently targeted, in contrast to the VJ region, where G nucleotides appeared to be mutational hotspots. The replacement/synonymous ratios in the VJ and C regions were 2.5 and 1.85, respectively. Only 7% of the mutations were found to be linked to the activation-induced cytidine deaminase hotspot motif (RGYW/WRCY).
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Somatic Hypermutation introduces a high frequency of amino acid substitutions in the constant region of the t cell receptor alpha chain in ballan wrasse labrus bergylta
Fish & Shellfish Immunology, 2016Co-Authors: Ivar Hordvik, Sumaira BilalAbstract:It was previously thought that T cell receptor genes were not subject to Somatic Hypermutation, which is in contrast to immunoglobulin genes where this mechanism is associated with a key role in the affinity maturation of the antibody response. However, recent studies in shark and camels have shown that variable T cell receptor gamma chain genes are hypermutated. In this presentation we show that Somatic mutations on the constant part of the T cell receptor alpha chain gene are frequent in a teleost fish; Ballan wrasse (Labrus bergylta). We examined many Tcra cDNAs from the same individual to determine if constant region diversity exceeded the amount that could be attributed to germline polymorphism. It is plausible to assume that Somatic Hypermutation is involved in the generation of the T cell repertoire and that consequently mutations are introduced in the constant region gene. The amino acid substitutions we found in Ballan wrasse are primarily positioned in the loops between the beta sheets, i.e. regions that apparently are not critical for the overall structure. It has been reported that polymorphism at the constant T cell receptor alpha chain genes is widespread in teleosts. After we had found several amino acid substitutions in translated cDNAs present in public databases the present study was initiated in an attempt to reveal corresponding polymorphism in Atlantic salmon (Salmo salar). Although we sequenced the gene in several individuals from rivers in Norway, Russia and Canada we only found some germline mutations in untranslated regions.
Ivar Hordvik - One of the best experts on this subject based on the ideXlab platform.
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t cell receptor alpha chain genes in the teleost ballan wrasse labrus bergylta are subjected to Somatic Hypermutation
Frontiers in Immunology, 2018Co-Authors: Sumaira Bilal, Kai Kristoffer Lie, Øystein Sæle, Ivar HordvikAbstract:Previously, Somatic Hypermutation (SHM) was considered to be exclusively associated with affinity maturation of antibodies, although it also occurred in T cells under certain conditions. More recently, it has been shown that SHM generates diversity in the variable domain of T cell receptor (TCR) in camel and shark. Here, we report Somatic mutations in TCR alpha chain genes of the teleost fish, Ballan wrasse (Labrus bergylta), and show that this mechanism adds extra diversity to the polymorphic constant (C) region as well. The organization of the TCR alpha/delta locus in Ballan wrasse was obtained from a scaffold covering a single copy C alpha gene, 65 putative J alpha segments, a single copy C delta gene, 1 J delta segment, and 2 D delta segments. Analysis of 37 fish revealed 6 allotypes of the C alpha gene, each with 1-3 replacement substitutions. Somatic mutations were analyzed by molecular cloning of TCR alpha chain cDNA. Initially, 79 unique clones comprising four families of variable (V) alpha genes were characterized. Subsequently, a more restricted PCR was performed to focus on a specific V gene. Comparison of 48 clones indicated that the frequency of Somatic mutations in the VJ region was 4.5/1,000 base pairs (bps), and most prevalent in complementary determining region 2 (CDR2). In total, 45 different J segments were identified among the 127 cDNA clones, counting for most of the CDR3 diversity. The number of mutations in the C alpha chain gene was 1.76 mutations/1,000 bps and A nucleotides were most frequently targeted, in contrast to the VJ region, where G nucleotides appeared to be mutational hotspots. The replacement/synonymous ratios in the VJ and C regions were 2.5 and 1.85, respectively. Only 7% of the mutations were found to be linked to the activation-induced cytidine deaminase hotspot motif (RGYW/WRCY).
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Somatic Hypermutation introduces a high frequency of amino acid substitutions in the constant region of the t cell receptor alpha chain in ballan wrasse labrus bergylta
Fish & Shellfish Immunology, 2016Co-Authors: Ivar Hordvik, Sumaira BilalAbstract:It was previously thought that T cell receptor genes were not subject to Somatic Hypermutation, which is in contrast to immunoglobulin genes where this mechanism is associated with a key role in the affinity maturation of the antibody response. However, recent studies in shark and camels have shown that variable T cell receptor gamma chain genes are hypermutated. In this presentation we show that Somatic mutations on the constant part of the T cell receptor alpha chain gene are frequent in a teleost fish; Ballan wrasse (Labrus bergylta). We examined many Tcra cDNAs from the same individual to determine if constant region diversity exceeded the amount that could be attributed to germline polymorphism. It is plausible to assume that Somatic Hypermutation is involved in the generation of the T cell repertoire and that consequently mutations are introduced in the constant region gene. The amino acid substitutions we found in Ballan wrasse are primarily positioned in the loops between the beta sheets, i.e. regions that apparently are not critical for the overall structure. It has been reported that polymorphism at the constant T cell receptor alpha chain genes is widespread in teleosts. After we had found several amino acid substitutions in translated cDNAs present in public databases the present study was initiated in an attempt to reveal corresponding polymorphism in Atlantic salmon (Salmo salar). Although we sequenced the gene in several individuals from rivers in Norway, Russia and Canada we only found some germline mutations in untranslated regions.
Matthew D. Scharff - One of the best experts on this subject based on the ideXlab platform.
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human immunodeficiency virus tat protein aids v region Somatic Hypermutation in human b cells
Mbio, 2018Co-Authors: Xiaohua Wang, Manxia Fan, Zhi Duan, Matthew D. ScharffAbstract:Long-term survivors of human immunodeficiency virus (HIV) infection have been shown to have a greatly increased incidence of B cell lymphomas. This increased lymphomagenesis suggests some link between HIV infection and the destabilization of the host B cell genome, a phenomenon also suggested by the extraordinary high frequency of mutation, insertion, and deletion in the broadly neutralizing HIV antibodies. Since HIV does not infect B cells, the molecular mechanisms of this genomic instability remain to be fully defined. Here, we demonstrate that the cell membrane-permeable HIV Tat proteins enhance activation-induced deaminase (AID)-mediated Somatic Hypermutation (SHM) of antibody V regions through their modulation of the endogenous polymerase II (Pol II) transcriptional process. Extremely small amounts of Tat that could come from bystander HIV-infected cells were sufficient to promote SHM. Our data suggest HIV Tat is one missing link between HIV infection and the overall B cell genomic instability in AIDS patients.IMPORTANCE Although the introduction of antiretroviral therapy (ART) has successfully controlled primary effects of human immunodeficiency virus (HIV) infection, such as HIV proliferation and HIV-induced immune deficiency, it did not eliminate the increased susceptibility of HIV-infected patients to B cell lymphomas. We find that a secreted HIV protein, Tat, enhances the intrinsic antibody diversification mechanism by increasing the AID-induced Somatic mutations at the heavy-chain variable (VH) regions in human B cells. This could contribute to the high rate of mutation in the variable regions of broadly neutralizing anti-HIV antibodies and the genomewide mutations leading to B cell malignancies in HIV carriers.
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altered Somatic Hypermutation and reduced class switch recombination in exonuclease 1 mutant mice
Nature Immunology, 2004Co-Authors: Philip Bardwell, Winfried Edelmann, Alberto Martin, Caroline J Woo, Kaichun Wei, Stephen Z Sack, Tchaiko Parris, Matthew D. ScharffAbstract:The generation of protective antibodies requires Somatic Hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin genes. Here we show that mice mutant for exonuclease 1 (Exo1), which participates in DNA mismatch repair (MMR), have decreased CSR and changes in the characteristics of SHM similar to those previously observed in mice mutant for the MMR protein Msh2. Exo1 is thus the first exonuclease shown to be involved in SHM and CSR. The phenotype of Exo1−/− mice and the finding that Exo1 and Mlh1 are physically associated with mutating variable regions support the idea that Exo1 and MMR participate directly in SHM and CSR.
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induction of Somatic Hypermutation is associated with modifications in immunoglobulin variable region chromatin
Immunity, 2003Co-Authors: Caroline J Woo, Alberto Martin, Matthew D. ScharffAbstract:Somatic Hypermutation (SHM) requires selective targeting of the mutational machinery to the variable region of the immunoglobulin heavy chain gene. The induction of SHM in the BL2 cell line upon costimulation is associated with hyperacetylation of the chromatin at the variable region but not at the constant region. The V region-restricted histone hyperacetylation resulting from costimulation occurs independent of AID expression and mutation. Interestingly, costimulation in the presence of Trichostatin A causes hyperacetylation of histones associated with the constant region and extends mutations to the constant region. Under this condition, promoter proximal mutations are observed in the variable region as well. The overexpression of AID results in a similar deregulation of mutational targeting. Our results indicate that the stimulation of SHM in BL2 cells activates two independent pathways resulting in histone modifications that permit induced levels of AID to selectively target the variable region for mutation.
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activation induced cytidine deaminase turns on Somatic Hypermutation in hybridomas
Nature, 2002Co-Authors: Alberto Martin, Philip Bardwell, Caroline J Woo, Manxia Fan, Marc J Shulman, Matthew D. ScharffAbstract:The production of high-affinity protective antibodies requires Somatic Hypermutation (SHM) of the antibody variable (V)-region genes. SHM is characterized by a high frequency of point mutations that occur only during the centroblast stage of B-cell differentiation. Activation-induced cytidine deaminase (AID), which is expressed specifically in germinal-centre centroblasts1, is required for this process, but its exact role is unknown2. Here we show that AID is required for SHM in the centroblast-like Ramos cells, and that expression of AID is sufficient to induce SHM in hybridoma cells, which represent a later stage of B-cell differentiation that does not normally undergo SHM. In one hybridoma, mutations were exclusively in G·C base pairs that were mostly within RGYW or WRCY motifs, suggesting that AID has primary responsibility for mutations at these nucleotides. The activation of SHM in hybridomas indicates that AID does not require other centroblast-specific cofactors to induce SHM, suggesting either that it functions alone or that the factors it requires are expressed at other stages of B-cell differentiation.
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Somatic Hypermutation in muts homologue msh 3 msh6 and msh3 msh6 deficient mice reveals a role for the msh2 msh6 heterodimer in modulating the base substitution pattern
Journal of Experimental Medicine, 2000Co-Authors: Margrit Wiesendanger, Burkhard Kneitz, Winfried Edelmann, Matthew D. ScharffAbstract:Although the primary function of the DNA mismatch repair (MMR) system is to identify and correct base mismatches that have been erroneously introduced during DNA replication, recent studies have further implicated several MMR components in Somatic Hypermutation of immunoglobulin (Ig) genes. We studied the immune response in mice deficient in MutS homologue (MSH)3 and MSH6, two mutually exclusive partners of MSH2 that have not been examined previously for their role in Ig Hypermutation. In Msh6−/− and Msh3−/−/Msh6−/− mice, base substitutions are preferentially targeted to G and C nucleotides and to an RGYW hot spot, as has been shown previously in Msh2−/− mice. In contrast, Msh3−/− mice show no differences from their littermate controls. These findings indicate that the MSH2–MSH6 heterodimer, but not the MSH2–MSH3 complex, is responsible for modulating Ig Hypermutation.
Martin F. Flajnik - One of the best experts on this subject based on the ideXlab platform.
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nurse shark t cell receptors employ Somatic Hypermutation preferentially to alter alpha delta variable segments associated with alpha constant region
European Journal of Immunology, 2020Co-Authors: Jeannine A Ott, Martin F. Flajnik, Michael F Criscitiello, Jenna HarrisonAbstract:In addition to canonical TCR and BCR, cartilaginous fish assemble noncanonical TCR that employ various B-cell components. For example, shark T cells associate alpha (TCR-α) or delta (TCR-δ) constant (C) regions with Ig heavy chain (H) variable (V) segments or TCR-associated Ig-like V (TAILV) segments to form chimeric IgV-TCR, and combine TCRδC with both Ig-like and TCR-like V segments to form the doubly rearranging NAR-TCR. Activation-induced (cytidine) deaminase-catalyzed Somatic Hypermutation (SHM), typically used for B-cell affinity maturation, also is used by TCR-α during selection in the shark thymus presumably to salvage failing receptors. Here, we found that the use of SHM by nurse shark TCR varies depending on the particular V segment or C region used. First, SHM significantly alters alpha/delta V (TCRαδV) segments using TCR αC but not δC. Second, mutation to IgHV segments associated with TCR δC was reduced compared to mutation to TCR αδV associated with TCR αC. Mutation was present but limited in V segments of all other TCR chains including NAR-TCR. Unexpectedly, we found preferential rearrangement of the noncanonical IgHV-TCRδC over canonical TCR αδV-TCRδC receptors. The differential use of SHM may reveal how activation-induced (cytidine) deaminase targets V regions.
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Somatic Hypermutation of t cell receptor α chain contributes to selection in nurse shark thymus
eLife, 2018Co-Authors: Jeannine A Ott, Martin F. Flajnik, Michael F Criscitiello, Yuko Ohta, Caitlin D Castro, Thaddeus C DeissAbstract:Since the discovery of the T cell receptor (TcR), immunologists have assigned Somatic Hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates.
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Somatic Hypermutation and junctional diversification at ig heavy chain loci in the nurse shark
Journal of Immunology, 2005Co-Authors: Karolina Malecek, Martin F. Flajnik, Yuko Ohta, Julie Brandman, Jennie E Brodsky, Ellen HsuAbstract:We estimate there are approximately 15 IgM H chain loci in the nurse shark genome and have characterized one locus. It consists of one V, two D, and one J germline gene segments, and the constant (C) region can be distinguished from all of the others by a unique combination of restriction endonuclease sites in Cmu2. On the basis of these Cmu2 markers, 22 cDNA clones were selected from an epigonal organ cDNA library from the same individual; their C region sequences proved to be the same up to the polyadenylation site. With the identification of the corresponding germline gene segments, CDR3 from shark H chain rearrangements could be analyzed precisely, for the first time. Considerable diversity was generated by trimming and N addition at the three junctions and by varied recombination patterns of the two D gene segments. The cDNA sequences originated from independent rearrangements events, and most carried both single and contiguous substitutions. The 53 point mutations occurred with a bias for transition changes (53%), whereas the 78 tandem substitutions, mostly 2-4 bp long, do not (36%). The nature of the substitution patterns is the same as for mutants from six loci of two nurse shark L chain isotypes, showing that Somatic Hypermutation events are very similar at both H and L chain genes in this early vertebrate. The cis-regulatory elements targeting Somatic Hypermutation must have already existed in the ancestral Ig gene, before H and L chain divergence.
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decreased frequency of Somatic Hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense rna to dna polymerase ζ
Journal of Immunology, 2001Co-Authors: Marilyn Diaz, Martin F. Flajnik, Laurent Verkoczy, Norman R KlinmanAbstract:To examine a role of DNA polymerase zeta in Somatic Hypermutation, we generated transgenic mice that express antisense RNA to a portion of mouse REV3, the gene encoding this polymerase. These mice express high levels of antisense RNA, significantly reducing the levels of endogenous mouse REV3 transcript. Following immunization to a hapten-protein complex, transgenic mice mounted vigorous Ab responses, accomplished the switch to IgG, and formed numerous germinal centers. However, in most transgenic animals, the generation of high affinity Abs was delayed. In addition, accumulation of Somatic mutations in the V(H) genes of memory B cells from transgenic mice was decreased, particularly among those that generate amino acid replacements that enhance affinity of the B cell receptor to the hapten. These data implicate DNA polymerase zeta, a nonreplicative polymerase, in the process of affinity maturation, possibly through a role in Somatic Hypermutation, clonal selection, or both.
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evolution and the molecular basis of Somatic Hypermutation of antigen receptor genes
Philosophical Transactions of the Royal Society B, 2001Co-Authors: Marilyn Diaz, Martin F. Flajnik, Norman R KlinmanAbstract:Somatic Hypermutation of immunoglobulin genes occurs in many vertebrates including sharks, frogs, camels, humans and mice. Similarities among species reveal a common mechanism and these include the AGC/T sequence hot spot, preponderance of base substitutions, a bias towards transitions and strand bias. There are some differences among species, however, that may unveil layers of the mechanism. These include a G:C bias in frog and shark IgM but not in nurse shark antigen receptor (NAR), a high frequency of doublets in NAR Hypermutation, and the co–occurrence of Somatic Hypermutation with gene conversion in some species. Here we argue that some of the similarities and differences among species are best explained by error–prone DNA synthesis by the translesion synthesis DNA polymerase zeta (Pol ζ) and, as suggested by others, induction of DNA synthesis by DNA breaks in antigen receptor variable genes. Finally, targeting of the variable genes is probably obtained via transcription–related elements, and it is the targeting phase of Somatic Hypermutation that is the most likely to reveal molecules unique to adaptive immunity.
