Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures

Steele, Edward J.

doi:10.1016/j.dnarep.2016.07.001

Cited by 22 publications

(35 citation statements)

References 210 publications

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“…However, the A and T mutations occur at different 2-nt long hot spots (80), suggesting an alternate mechanism of mutation. There are two hotly debated theories of the mechanism underlying A and T mutations (89). One theory proposes that adenosine deaminase that acts on RNA (ADAR) converts adenosine to inosine, which occurs at a different hot spot and introduces A mutations mostly on the coding DNA strand (50, 67, 89).…”

Section: Resultsmentioning

confidence: 99%

“…There are two hotly debated theories of the mechanism underlying A and T mutations (89). One theory proposes that adenosine deaminase that acts on RNA (ADAR) converts adenosine to inosine, which occurs at a different hot spot and introduces A mutations mostly on the coding DNA strand (50, 67, 89). The other theory assumes that the AID-induced U:G mismatch triggers multiple DNA repair enzymes to eventually introduce A:T mutations nearby (51, 90, 91).…”

Section: Resultsmentioning

confidence: 99%

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BRILIA: Integrated Tool for High-Throughput Annotation and Lineage Tree Assembly of B-Cell Repertoires

et al. 2017

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The somatic diversity of antigen-recognizing B-cell receptors (BCRs) arises from Variable (V), Diversity (D), and Joining (J) (VDJ) recombination and somatic hypermutation (SHM) during B-cell development and affinity maturation. The VDJ junction of the BCR heavy chain forms the highly variable complementarity determining region 3 (CDR3), which plays a critical role in antigen specificity and binding affinity. Tracking the selection and mutation of the CDR3 can be useful in characterizing humoral responses to infection and vaccination. Although tens to hundreds of thousands of unique BCR genes within an expressed B-cell repertoire can now be resolved with high-throughput sequencing, tracking SHMs is still challenging because existing annotation methods are often limited by poor annotation coverage, inconsistent SHM identification across the VDJ junction, or lack of B-cell lineage data. Here, we present B-cell repertoire inductive lineage and immunosequence annotator (BRILIA), an algorithm that leverages repertoire-wide sequencing data to globally improve the VDJ annotation coverage, lineage tree assembly, and SHM identification. On benchmark tests against simulated human and mouse BCR repertoires, BRILIA correctly annotated germline and clonally expanded sequences with 94 and 70% accuracy, respectively, and it has a 90% SHM-positive prediction rate in the CDR3 of heavily mutated sequences; these are substantial improvements over existing methods. We used BRILIA to process BCR sequences obtained from splenic germinal center B cells extracted from C57BL/6 mice. BRILIA returned robust B-cell lineage trees and yielded SHM patterns that are consistent across the VDJ junction and agree with known biological mechanisms of SHM. By contrast, existing BCR annotation tools, which do not account for repertoire-wide clonal relationships, systematically underestimated both the size of clonally related B-cell clusters and yielded inconsistent SHM frequencies. We demonstrate BRILIA’s utility in B-cell repertoire studies related to VDJ gene usage, mechanisms for adenosine mutations, and SHM hot spot motifs. Furthermore, we show that the complete gene usage annotation and SHM identification across the entire CDR3 are essential for studying the B-cell affinity maturation process through immunosequencing methods.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

BRILIA: Integrated Tool for High-Throughput Annotation and Lineage Tree Assembly of B-Cell Repertoires

et al. 2017

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“…To explain their data, they invoked the idea of an mRNA template being necessary to encode H‐2 Class I/II intermediates and reverse transcription as the most economical explanation for the complex mosaic tract patterns observed . The role for reverse transcription involving an mRNA intermediary has been previously discussed by us in SHM itself and will be discussed further below …”

Section: Why Should the Tcr Somatically Mutate?mentioning

confidence: 97%

“…20 The role for reverse transcription involving an mRNA intermediary has been previously discussed by us in SHM itself and will be discussed further below. [23][24][25][26][27][28]…”

Section: Somatically Mutate?mentioning

confidence: 99%

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

Steele¹,

Lindley

2019

Scand J Immunol

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What is the evolutionary mechanism for the TCR‐MHC‐conserved interaction? We extend Dembic's model (Dembic Z. In, Scand J Immunol e12806, 2019) of thymus positive selection for high‐avidity anti–self‐MHC Tregs among double (CD4 + CD8+)‐positive (DP) developing thymocytes. This model is based on competition for self‐MHC (+ Pep) complexes presented on cortical epithelium. Such T cells exit as CD4 + CD25+FoxP3 + thymic‐derived Tregs (tTregs). The other positively selected DP T cells are then negatively selected on medulla epithelium removing high‐avidity anti–self‐MHC + Pep as T cells commit to CD4 + or CD8 + lineages. The process is likened to the competitive selection and affinity maturation in Germinal Centre for the somatic hypermutation (SHM) of rearranged immunoglobulin (Ig) variable region (V[D]Js) of centrocytes bearing antigen‐specific B cell receptors (BCR). We now argue that the same direct SHM processes for TCRs occur in post‐antigenic Germinal Centres, but now occurring in peripheral pTregs. This model provides a potential solution to a long‐standing problem previously recognized by Cohn and others (Cohn M, Anderson CC, Dembic Z. In, Scand J Immunol e12790, 2019) of how co‐evolution occurs of species‐specific MHC alleles with the repertoire of their germline TCR V counterparts. We suggest this is not by ‘blind’, slow, and random Darwinian natural selection events, but a rapid structured somatic selection vertical transmission process. The pTregs bearing somatic TCR V mutant genes then, on arrival in reproductive tissues, can donate their TCR V sequences via soma‐to‐germline feedback as discussed in this journal earlier. (Steele EJ, Lindley RA. In, Scand J Immunol e12670, 2018) The high‐avidity tTregs also participate in the same process to maintain a biased, high‐avidity anti–self‐MHC germline V repertoire.

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“…a) The basic mechanisms of B and T cell adaptive immunity are very similar; in particular the mechanisms of immunoglobulin variable (V) to diversity (D) and joining (J) element rearrangements and the mechanism of somatic hypermutation, reviewed in Steele and the basic similarities between the immunogenetics of Ig and T cell receptors (TCRs, see text Murphy et al) [1][2][3].…”

Section: Mouse Cancer Models Often Failmentioning

confidence: 99%

Deaminases and Why Mice Sometimes Lie in Immuno-Oncology Pre-Clinical Trials?

Steele¹,

Lindley²

2019

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A B S T R A C TThere is now much evidence for the involvement of deaminase-mediated somatic mutagenesis during cancer progression. These developments lead us to reappraise the likely impact of AID/APOBEC and ADAR deaminases in human cancer progression with their expected lesser impact on somatic mutagenesis in mouse cancer model systems. The findings are important for pre-clinical trials of immune oncology (IO) drugs activating adaptive immune responses against tumor cells. Our conclusions are consistent with, and underline, recent recommendations by Decker and colleagues that IO pre-clinical trials should at least include therapies against spontaneous tumors in dogs. While the AID/APOBEC deaminase specificity repertoire in dogs is likely to be less than in humans, it will be far greater than in the mouse and thus more likely to better mimic dysregulated Ig like somatic hypermutation responses during cancer progression in humans.

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Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures

Cited by 22 publications

References 210 publications

BRILIA: Integrated Tool for High-Throughput Annotation and Lineage Tree Assembly of B-Cell Repertoires

BRILIA: Integrated Tool for High-Throughput Annotation and Lineage Tree Assembly of B-Cell Repertoires

Regulatory T cells and co‐evolution of allele‐specific MHC recognition by the TCR

Deaminases and Why Mice Sometimes Lie in Immuno-Oncology Pre-Clinical Trials?

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