英国剑桥大学Serena Nik-Zainal课题组提出了重新定义的InDel分类法提供了对突变特征的深入了解。这一研究成果发表在2025年4月10日出版的国际学术期刊《自然—遗传学》上。

在这里，该课题组生成了等基因CRISPR编辑的复制后修复功能障碍（PRRd）的人类细胞模型，包括DNA错配修复（MMR）和复制聚合酶（Pol ε和Pol δ）的单独和联合基因编辑。揭示了独特的、多样的InDel突变足迹。

然而，现行的InDel分类框架无法区分这些InDel特征与背景突变以及彼此之间的差异。为了解决这个问题，该课题组研究人员开发了另一种InDel分类系统，该系统考虑了侧翼序列和信息基序（例如，更长的均聚物），使它们能够明确地分为89个InDel亚型。通过对来自10万基因组计划的7种肿瘤类型的焦点主题表征，该课题组人员发现了37个InDel特征（其中27个是新发现）。除了揭示以前隐藏的生物学见解外，研究小组还开发了PRRDetect -一种高度特异性的肿瘤PRRd状态分类器，具有潜在的免疫治疗意义。

据悉，尽管小片段插入与缺失（InDel）具有显著的遗传危害性，但其研究关注度远不及碱基替换。

附：英文原文

Title: A redefined InDel taxonomy provides insights into mutational signatures

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

Issue&Volume: 2025-04-10

Abstract: 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.

DOI: 10.1038/s41588-025-02152-y

Source: https://www.nature.com/articles/s41588-025-02152-y