Utilizing insights of DNA repair machinery to discover MMEJ deletions and novel mechanisms

Aditee Kadam, Shay Shilo, Hadas Naor, Alexander Wainstein, Yardena Brilon, Tzah Feldman, Mark Minden, Nathali Kaushansky, Noa Chapal-Ilani, Liran Shlush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We developed Del-read, an algorithm targeting medium-sized deletions (6-100 bp) in short-reads, which are challenging for current variant callers relying on alignment. Our focus was on Micro-Homolog mediated End Joining deletions (MMEJ-dels), prevalent in myeloid malignancies. MMEJ-dels follow a distinct pattern, occurring between two homologies, allowing us to generate a comprehensive list of MMEJ-dels in the exome. Using Del-read, we identified numerous novel germline and somatic MMEJ-dels in BEAT-AML and TCGA-breast datasets. Validation in 672 healthy individuals confirmed their presence. These novel MMEJ-dels were linked to genomic features associated with replication stress, like G-quadruplexes and minisatellite. Additionally, we observed a new category of MMEJ-dels with an imperfect-match at the flanking sequences of the homologies, suggesting a mechanism involving mispairing in homology alignment. We demonstrated robustness of the repair system despite CRISPR/Cas9-induced mismatches in the homologies. Further analysis of the canonical ASXL1 deletion revealed a diverse array of these imperfect-matches. This suggests a potentially more flexible and error-prone MMEJ repair system than previously understood. Our findings highlight Del-read's potential in uncovering previously undetected deletions and deepen our understanding of repair mechanisms.

Original languageEnglish
Article numbere106
JournalNucleic Acids Research
Volume52
Issue number22
Early online date28 Nov 2024
DOIs
Publication statusPublished - 11 Dec 2024

Funding

Rising Tide Foundation [isf-nsfc 2427/18, rtf6005-19]; Steven B. Rubenstein research fund; Applebaum Foundation; Ernest and Bonnie Beutler Research Program; Sagol Institute for Longevity Research; Barry and Eleanore Reznik Family Cancer Research fund; ISF-IPMP-Israel Precision Medicine Program [1123/21, 3165/19]. Funding for open access charge: L.L.S. and Rising Tide Foundation [rtf6005-19, isf-nsfc 2427/18, isf-ipmp-israel precision medicine program 3165/19, isf 1123/21]; Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; L.S. is an incumbent of the Ruth and Louis Leland Career Development Chair; Sagol Institute for Longevity Research; Barry and Eleanore Reznik Family Cancer Research fund; Steven B. Rubenstein Research Fund for Leukemia and other blood disorders; Rising Tide Foundation and the Applebaum Foundation.

All Science Journal Classification (ASJC) codes

  • Genetics

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