{"doi":"10.1101/2023.02.19.526140","title":"Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing","abstract":"Abstract Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases 1-4 . Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired 5 . However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":390489,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.946,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1162268,"name":"Benjamin M. Costa","orcid":"0009-0004-2320-090X","position":1,"is_corresponding":false},{"id":641159,"name":"Una Choi","orcid":null,"position":2,"is_corresponding":false},{"id":624449,"name":"Rachel C. Bandler","orcid":null,"position":3,"is_corresponding":false},{"id":1022266,"name":"Emilie Lassen","orcid":"0000-0002-1484-2028","position":4,"is_corresponding":false},{"id":417611,"name":"Marta Grońska-Pęski","orcid":"0000-0001-9965-8520","position":5,"is_corresponding":false},{"id":1162780,"name":"Adam Schwing","orcid":null,"position":6,"is_corresponding":false},{"id":966587,"name":"Zachary R. Murphy","orcid":"0000-0003-3017-7248","position":7,"is_corresponding":false},{"id":1162269,"name":"Daniel Rosenkjær","orcid":"0000-0001-6032-2202","position":8,"is_corresponding":false},{"id":1162781,"name":"Shany Picciotto","orcid":null,"position":9,"is_corresponding":false},{"id":1162270,"name":"Vanessa Bianchi","orcid":"0009-0009-0187-3659","position":10,"is_corresponding":false},{"id":1162271,"name":"Lucie Stengs","orcid":"0009-0007-5125-398X","position":11,"is_corresponding":false},{"id":393460,"name":"Melissa Edwards","orcid":"0000-0001-5445-4671","position":12,"is_corresponding":false},{"id":1162272,"name":"Caitlin A. Loh","orcid":"0009-0006-7305-3885","position":13,"is_corresponding":false},{"id":381646,"name":"Tina K. Truong","orcid":"0009-0004-0871-1082","position":14,"is_corresponding":false},{"id":294318,"name":"Randall E. Brand","orcid":"0000-0002-4136-3313","position":15,"is_corresponding":false},{"id":51475,"name":"Tomi Pastinen","orcid":"0000-0003-4016-5021","position":16,"is_corresponding":false},{"id":513359,"name":"J. Richard Wagner","orcid":"0000-0002-0240-2324","position":17,"is_corresponding":false},{"id":1022267,"name":"Anne‐Bine Skytte","orcid":"0000-0002-0067-9557","position":18,"is_corresponding":false},{"id":240510,"name":"Uri Tabori","orcid":"0000-0002-5019-2683","position":19,"is_corresponding":false},{"id":581206,"name":"Jonathan E. Shoag","orcid":"0000-0002-3119-9986","position":20,"is_corresponding":false},{"id":68981,"name":"Gilad D. Evrony","orcid":"0000-0001-7621-2630","position":21,"is_corresponding":false},{"id":1023324,"name":"Mei Hong Liu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":135,"raw_metadata":null,"created_at":"2026-07-19T01:18:37.743462Z","pmid":"36824744","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}