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A high-resolution landscape of mutations in the super-enhancer in normal human B cells. | LitMetric

AI Article Synopsis

  • Super-enhancers (SEs) in B cells are sites for somatic hypermutation, but the study achieved high-resolution analysis of these mutations in healthy individuals for the first time.
  • Researchers captured and sequenced 12 B cell SEs, uncovering around 9,000 subclonal mutations, with most mutations unique to the SE itself.
  • The study also identified specific mutational signatures linked to the activity of certain enzymes, suggesting their role in mutagenesis, and highlights the potential for using these mutations for early detection of B cell cancers.

Article Abstract

The super-enhancers (SEs) of lineage-specific genes in B cells are off-target sites of somatic hypermutation. However, the inability to detect sufficient numbers of mutations in normal human B cells has precluded the generation of a high-resolution mutational landscape of SEs. Here we captured and sequenced 12 B cell SEs at single-nucleotide resolution from 10 healthy individuals across diverse ethnicities. We detected a total of approximately 9,000 subclonal mutations (allele frequencies <0.1%); of these, approximately 8,000 are present in the SE alone. Within the SE, we identified 3 regions of clustered mutations in which the mutation frequency is ∼7 × 10 Mutational spectra show a predominance of C > T/G > A and A > G/T > C substitutions, consistent with the activities of activation-induced-cytidine deaminase (AID) and the A-T mutator, DNA polymerase η, respectively, in mutagenesis in normal B cells. Analyses of mutational signatures further corroborate the participation of these factors in this process. Single base substitution signatures SBS85, SBS37, and SBS39 were found in the SE. While SBS85 is a denoted signature of AID in lymphoid cells, the etiologies of SBS37 and SBS39 are unknown. Our analysis suggests the contribution of error-prone DNA polymerases to the latter signatures. The high-resolution mutation landscape has enabled accurate profiling of subclonal mutations in B cell SEs in normal individuals. By virtue of the fact that subclonal SE mutations are clonally expanded in B cell lymphomas, our studies also offer the potential for early detection of neoplastic alterations.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900602PMC
http://dx.doi.org/10.1073/pnas.1914163116DOI Listing

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