{"doi":"10.1099/mgen.0.000724","title":"Whole genome sequencing reveals large deletions and other loss of function mutations in Mycobacterium tuberculosis drug resistance genes","abstract":"<jats:p>Drug resistance in <jats:italic>\n                     <jats:named-content content-type=\"species\">\n                        <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"http://doi.org/10.1601/nm.10886\" xlink:type=\"simple\">Mycobacterium tuberculosis</jats:ext-link>\n                     </jats:named-content>\n                  </jats:italic>, the causative agent of tuberculosis disease, arises from genetic mutations in genes coding for drug-targets or drug-converting enzymes. SNPs linked to drug resistance have been extensively studied and form the basis of molecular diagnostics and sequencing-based resistance profiling. However, alternative forms of functional variation such as large deletions and other loss of function (LOF) mutations have received much less attention, but if incorporated into diagnostics they are likely to improve their predictive performance. Our work aimed to characterize the contribution of LOF mutations found in 42 established drug resistance genes linked to 19 anti-tuberculous drugs across 32689 sequenced clinical isolates. The analysed LOF mutations included large deletions (<jats:italic>n</jats:italic>=586), frameshifts (<jats:italic>n</jats:italic>=4764) and premature stop codons (<jats:italic>n</jats:italic>=826). We found LOF mutations in genes strongly linked to pyrazinamide (<jats:italic>pncA</jats:italic>), isoniazid (<jats:italic>katG</jats:italic>), capreomycin (<jats:italic>tlyA</jats:italic>), streptomycin (e.g. <jats:italic>gid</jats:italic>) and ethionamide (<jats:italic>ethA, mshA</jats:italic>) (<jats:italic>P</jats:italic>&lt;10<jats:sup>−5</jats:sup>), but also in some loci linked to drugs where relatively less phenotypic data is available [e.g. cycloserine, delaminid, bedaquiline, <jats:italic>para</jats:italic>-aminosalicylic acid (PAS), and clofazimine]. This study reports that large deletions (median size 1115 bp) account for a significant portion of resistance variants found for PAS (+7.1% of phenotypic resistance percentage explained), pyrazinamide (+3.5%) and streptomycin (+2.6%) drugs, and can be used to improve the prediction of cryptic resistance. Overall, our work highlights the importance of including LOF mutations (e.g. large deletions) in predicting genotypic drug resistance, thereby informing tuberculosis infection control and clinical decision-making.</jats:p>","journal":"Microbial Genomics","year":2021,"id":600252,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":249966,"name":"Susana Campino","orcid":"0000-0003-1403-6138","position":1,"is_corresponding":false},{"id":791152,"name":"Cláudio Romero Farias Marinho","orcid":"0000-0002-1227-3845","position":2,"is_corresponding":false},{"id":19939,"name":"Taane G. Clark","orcid":"0000-0001-8985-9265","position":3,"is_corresponding":false},{"id":249970,"name":"Jody Phelan","orcid":"0000-0001-8323-7019","position":4,"is_corresponding":false},{"id":975560,"name":"Laura Cordeiro Gomes","orcid":"0000-0002-7161-0098","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Whole genome sequencing reveals large deletions and other loss of function mutations in Mycobacterium tuberculosis drug resistance genes","abstract":"<jats:p>Drug resistance in <jats:italic>\n                     <jats:named-content content-type=\"species\">\n                        <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"http://doi.org/10.1601/nm.10886\" xlink:type=\"simple\">Mycobacterium tuberculosis</jats:ext-link>\n                     </jats:named-content>\n                  </jats:italic>, the causative agent of tuberculosis disease, arises from genetic mutations in genes coding for drug-targets or drug-converting enzymes. SNPs linked to drug resistance have been extensively studied and form the basis of molecular diagnostics and sequencing-based resistance profiling. However, alternative forms of functional variation such as large deletions and other loss of function (LOF) mutations have received much less attention, but if incorporated into diagnostics they are likely to improve their predictive performance. Our work aimed to characterize the contribution of LOF mutations found in 42 established drug resistance genes linked to 19 anti-tuberculous drugs across 32689 sequenced clinical isolates. The analysed LOF mutations included large deletions (<jats:italic>n</jats:italic>=586), frameshifts (<jats:italic>n</jats:italic>=4764) and premature stop codons (<jats:italic>n</jats:italic>=826). We found LOF mutations in genes strongly linked to pyrazinamide (<jats:italic>pncA</jats:italic>), isoniazid (<jats:italic>katG</jats:italic>), capreomycin (<jats:italic>tlyA</jats:italic>), streptomycin (e.g. <jats:italic>gid</jats:italic>) and ethionamide (<jats:italic>ethA, mshA</jats:italic>) (<jats:italic>P</jats:italic>&lt;10<jats:sup>−5</jats:sup>), but also in some loci linked to drugs where relatively less phenotypic data is available [e.g. cycloserine, delaminid, bedaquiline, <jats:italic>para</jats:italic>-aminosalicylic acid (PAS), and clofazimine]. This study reports that large deletions (median size 1115 bp) account for a significant portion of resistance variants found for PAS (+7.1% of phenotypic resistance percentage explained), pyrazinamide (+3.5%) and streptomycin (+2.6%) drugs, and can be used to improve the prediction of cryptic resistance. Overall, our work highlights the importance of including LOF mutations (e.g. large deletions) in predicting genotypic drug resistance, thereby informing tuberculosis infection control and clinical decision-making.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34889724","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"bloomsbury set","grant_id":"BSA33","title":null},{"funder_name":"medical research council","grant_id":"MR/M01360X/1","title":"Geographic genetic profiling of human Plasmodium malaria"},{"funder_name":"medical research council","grant_id":"MR/N010469/1","title":"Understanding the transmission of tuberculosis using Mycobacterium tuberculosis sequence data"},{"funder_name":"medical research council","grant_id":"MR/R025576/1","title":"Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in the Philippines"},{"funder_name":"medical research council","grant_id":"MR/R020973/1","title":"Using whole genome sequencing to characterise drug resistant Mycobacterium tuberculosis in Thailand"},{"funder_name":"biotechnology and biological sciences research council","grant_id":"BB/R013063/1","title":"Using genomics to trace Salmonella transmission and antimicrobial resistance (AMR) in the poultry and swine food chains in the Philippines"}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1099/mgen.0.000724","host_type":"publisher"},{"url":"https://www.microbiologyresearch.org/content/journal/mgen/10.1099/mgen.0.000724?crawler=true&mimetype=application/pdf","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8767347","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34889724","host_type":""},{"url":"http://dx.doi.org/10.1099/mgen.0.000724","host_type":""}],"fields_of_study":["0301 basic medicine","03 medical and health sciences","Anti-Bacterial Agents","Codon, Nonsense","Drug Resistance, Bacterial","Frameshift Mutation","Genome, Bacterial","High-Throughput Nucleotide Sequencing","Humans","Loss of Function Mutation","Mycobacterium tuberculosis","Sequence Deletion","Whole Genome Sequencing"],"mesh_terms":["Anti-Bacterial Agents","Codon, Nonsense","Drug Resistance, Bacterial","Frameshift Mutation","Genome, Bacterial","High-Throughput Nucleotide Sequencing","Humans","Loss of Function Mutation","Mycobacterium tuberculosis","Sequence Deletion","Whole Genome Sequencing"],"keywords":["Whole Genome Sequencing","Short Communications","High-Throughput Nucleotide Sequencing","Mycobacterium tuberculosis","Anti-Bacterial Agents","Codon, Nonsense","Loss of Function Mutation","Drug Resistance, Bacterial","Humans","Frameshift Mutation","Genome, Bacterial","Sequence Deletion","WGS","antimicrobial resistance","tuberculosis"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-29T12:37:00.953563Z","pmid":null,"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":[]}