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 language | English |
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Article number | e106 |
Journal | Nucleic Acids Research |
Volume | 52 |
Issue number | 22 |
Early online date | 28 Nov 2024 |
DOIs | |
Publication status | Published - 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