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<p>Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect—a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.</p>

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A redefined InDel taxonomy provides insights into mutational signatures

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月10日

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  • Gene Ching Chiek Koh,
  • Arjun Scott Nanda,
  • Giuseppe Rinaldi,
  • Soraya Boushaki,
  • Andrea Degasperi,
  • Cherif Badja,
  • Andrew Marcel Pregnall,
  • Salome Jingchen Zhao,
  • Lucia Chmelova,
  • Daniella Black,
  • Laura Heskin,
  • João Dias,
  • Jamie Young,
  • Yasin Memari,
  • Scott Shooter,
  • Jan Czarnecki,
  • Matthew Arthur Brown,
  • Helen Ruth Davies,
  • Xueqing Zou,
  • Serena Nik-Zainal

摘要

Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect—a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.