{"doi":"10.1101/2025.01.27.635038","title":"MUSICiAn: Genome-wide Identification of Genes Involved in DNA Repair via Control-Free Mutational Spectra Analysis","abstract":"Motivation: Understanding the factors involved in DNA double-strand break (DSB) repair is crucial for the development of targeted anti-cancer therapies, yet the roles of many genes remain unclear. Recent studies show that perturbations of certain genes can alter the distribution of sequence-specific mutations left behind after DSB repair. This suggests that genome-wide screening could reveal novel DSB repair factors by identifying genes whose perturbation causes the mutational distribution spectra observed at a given DSB site to deviate significantly from the wild-type. However, designing proper controls for a genome-wide perturbation screen could be challenging. We explore the idea that a genome-wide screen might allow us to forgo the use of traditional non-targeting controls by reframing the analysis as an outlier detection problem, assuming that most genes have minimal influence on DSB repair. Results: We propose MUSICiAn (Mutational Signature Catalogue Analysis), a compositional data analysis method that ranks gene perturbation-specific mutational spectra without controls by measuring deviations from the central tendency in the distributions of all spectra. We show that MUSICiAn can effectively estimate pseudo-controls for the existing Repair-seq dataset, screening 476 genes and 60 non-targeting controls. We further apply MUSICiAn to a genome-wide dataset profiling mutational outcomes induced by CRISPR-Cas9 at three target sites across cells with individual perturbations of 18,406 genes. MUSICiAn successfully recovers known genes, highlights the spliceosome as a lesser-appreciated player in DSB repair, and reveals candidates for further investigation. Availability: github.com/joanagoncalveslab/MUSICiAn.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555381,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1453680,"name":"Marco Barazas","orcid":"0000-0002-4497-6000","position":1,"is_corresponding":false},{"id":317638,"name":"Robin van Schendel","orcid":"0000-0001-7068-0679","position":2,"is_corresponding":false},{"id":317640,"name":"Marcel Tijsterman","orcid":"0000-0001-8465-9002","position":3,"is_corresponding":false},{"id":571697,"name":"Joana P. Gonçalves","orcid":"0000-0001-6072-9627","position":4,"is_corresponding":false},{"id":1095021,"name":"Colm Seale","orcid":"0000-0003-1716-8419","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:59.329539Z","pmid":"39975194","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":[]}