A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

Álvarez-Prado, Ángel F.; Pérez-Durán, Pablo; Pérez-García, Arantxa; Benguría, Alberto; Torroja, Carlos; Yébenes, Virginia G. de; Ramiro, Almudena R.

doi:10.1084/jem.20171738

Cited by 87 publications

(114 citation statements)

References 46 publications

(93 reference statements)

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“…1D show the position-wise corrected mutation frequencies in both Aicda 2/2 (top) and wt GC B cells (bottom). Data processing gives a reassessment of the mutation rate in Cd83 and Bcl6 genomic regions in agreement with biological considerations and previously reported values by both the Schatz and Ramiro groups (8,9). We further tested whether the use of mouse tail tissue (lacking AID expression) could serve as a mutationfree control in HTS datasets for the Cd83 region.…”

Section: Sequencing Error Correction With Deminersupporting

confidence: 69%

“…Extensive DNA sequencing of mouse GC B cells by the Sanger method (8) and more recently by highthroughput sequencing (HTS) (9) highlighted distinct levels of protection in AID-expressing B cells by demonstrating that a consequent proportion of transcribed genes accumulated AID-induced somatic mutations. The majority of AID off-targets in the mouse display mutations at very low frequencies (,100-fold lower than SHM at Ig genes) because they were probably monitored by errorfree DNA repair, whereas some others, including Bcl6 and Cd83 loci, were more targeted (∼20-40-fold lower than Ig loci) (8,9).…”

Section: Detecting Rare Aid-induced Mutations In B-lineage Oncogenes mentioning

confidence: 99%

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Detecting Rare AID-Induced Mutations in B-Lineage Oncogenes from High-Throughput Sequencing Data Using the Detection of Minor Variants by Error Correction Method

Martin

Garot

Noir

et al. 2018

The Journal of Immunology

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In B-lineage cells, the cytidine deaminase AID not only generates somatic mutations to variable regions of Ig genes but also inflicts, at a lower frequency, mutations to several non-Ig genes named AID off-targets, which include proto-oncogenes. High-throughput sequencing should be in principle the method of choice to detect and document these rare nucleotide substitutions. So far, high-throughput sequencing-based methods are impaired by a global sequencing error rate that usually covers the real mutation rate of AID off-target genes in activated B cells. We demonstrate the validity of a per-base background subtraction method called detection of minor variants by error correction (DeMinEr), which uses deep sequencing data from mutated and nonmutated samples to correct the substitution frequency at each nucleotide position along the sequenced region. Our DeMinEr method identifies somatic mutations at a frequency down to 0.02% at any nucleotide position within two off-target genes: and Biological models and control conditions such as AID- and UNG-deficient mice validate the specificity and the sensitivity of our method. The high resolution and robustness of DeMinEr enable us to document fine effects such as age-dependent accumulation of mutations in these oncogenes in the mouse.

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Section: Sequencing Error Correction With Deminersupporting

confidence: 69%

Section: Detecting Rare Aid-induced Mutations In B-lineage Oncogenes mentioning

confidence: 99%

Detecting Rare AID-Induced Mutations in B-Lineage Oncogenes from High-Throughput Sequencing Data Using the Detection of Minor Variants by Error Correction Method

Martin

Garot

Noir

et al. 2018

The Journal of Immunology

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“…The preferred target of AID is the C embedded in the 'hotspot' WRCY motif (RGYW on the opposite strand; W = A/T, R = A/G, Y = C/T) (Álvarez-Prado et al, 2018;Rogozin and Kolchanov, 1992). Processing of the dUs results in base substitutions and/or DNA double strand breaks (DSBs), which is largely determined by the ensuing DNA repair activities (Bahjat and Guikema, 2017;Peled et al, 2008;Stavnezer et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

DNA polymerase β prevents AID-instigated mutagenic non-canonical mismatch DNA repair

Bahjat

Stratigopoulou

Pilzecker

et al. 2020

Preprint

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In B cells, the error-prone repair of activation-induced cytidine deaminase (AID)-induced lesions in immunoglobulin variable genes cause somatic hypermutation (SHM) of antibody genes. Due to clonal selection in the germinal centers (GC) this active mutation process provides the molecular basis for antibody affinity maturation. AID deaminates cytosine (C) to create uracil (U) in DNA. Typically, the short patch base excision repair (spBER) effectively restores genomic U lesions. We here demonstrate that GC B cells actively degrade DNA polymerase β (Polβ), resulting in the inactivation of the gap-filling step of spBER. Consequently, lesions instigated by AID, and likely other base damages, are channeled towards mutagenic non-canonical mismatch repair (mncMMR), responsible for the vast majority of mutations at adenine and thymine (A:T) bases. Apparently, GC B cells prohibit faithful spBER, thereby favoring A:T mutagenesis during SHM. Lastly, our data suggest that the loss of Polβ relates to hypoxia that characterizes the GC microenvironment.

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“…Álvarez-Prado et al (2018) also determined that both base excision repair (BER) and mismatch repair (MMR) pathways contribute to reducing mutations at off-target sites (see figure). From their data, it appears nevertheless that error-free repair takes place with a gradient of efficiency at different genes rather than being an all-or-none process that would discriminate mutations at off-target sites from the ones at the Ig loci.…”

mentioning

confidence: 99%

Predicting AID off-targets: A step forward

Reynaud

Weill

2018

Journal of Experimental Medicine

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A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

Abstract: Álvarez-Prado et al. report a detailed map of AID-induced off-target mutations and identify molecular features that predict gene mutability. They identify a novel AID hotspot and demonstrate that base excision and mismatch repair back up each other to repair most AID deamination events.

Cited by 87 publications

References 46 publications

Detecting Rare AID-Induced Mutations in B-Lineage Oncogenes from High-Throughput Sequencing Data Using the Detection of Minor Variants by Error Correction Method

Detecting Rare AID-Induced Mutations in B-Lineage Oncogenes from High-Throughput Sequencing Data Using the Detection of Minor Variants by Error Correction Method

DNA polymerase β prevents AID-instigated mutagenic non-canonical mismatch DNA repair

Predicting AID off-targets: A step forward

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