biostudies-literatureKadam AErnest and Bonnie Beutler Research ProgramISF-IPMP-Israel Precision Medicine ProgramRising Tide FoundationSteven B. Rubenstein research fundBarry and Eleanore Reznik Family Cancer Research fundSagol Institute for Longevity ResearchApplebaum Foundatione106https://www.ebi.ac.uk/biostudies/studies/S-EPMC11662932biostudies-literatureUnknown52(22)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-Nucleic acids researchUtilizing insights of DNA repair machinery to discover MMEJ deletions and novel mechanisms.PMC11662932rtf6005-193165/19isf-nsfc 2427/181123/21Chapal-Ilani NKadam AShlush LWainstein AMinden MFeldman TKaushansky NNaor HShilo SBrilon YfalseUtilizing insights of DNA repair machinery to discover MMEJ deletions and novel mechanisms.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-2024-01-01T00:00:00Z2024 Dec2025-04-18T12:52:29.041Z2025-04-06T22:14:19.768ZS-EPMC116629323960770510.1093/nar/gkae1132