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Understanding the genetic diversity of circulating MTBC strains is essential for improving diagnosis, surveillance and treatment strategies. In this study, we characterise the population structure and drug resistance landscape of MTBC strains circulating in The Gambia over nearly two decades (2002\u20132021). We analysed whole-genome sequencing (WGS) data from 1,803\u00a0TB isolates. Lineage 4 (L4) was predominant (67.2%), followed by the West Africa-restricted lineage 6 (L6, 26.6%), with L4 exhibiting greater genetic diversification over time. Drug susceptibility profiling of these isolates revealed that 78% (1421\/1803) were drug-susceptible, while 6.5% (119\/1803) harboured resistance to first-line drugs, primarily to isoniazid, rifampicin, or both. Notably, 15.5% (282\/1803) isolates carried mutations classified as having uncertain significance according to the WHO resistance catalogue. Comparative analyses revealed a lineage 6-specific ethambutol-associated mutation of uncertain significance (\n                    <jats:italic>em<\/jats:italic>\n                    bC Ala307Thr) occurring at a higher frequency in Gambian isolates than in the broader West Africa region or globally. Structural modelling demonstrated that many first-line drug resistance mutations are located in highly conserved, solvent-inaccessible regions of target proteins, often impacting protein stability, suggesting a trade-off between drug resistance, bacterial fitness, and evolutionary adaptation. Together, these findings highlight the coexistence of globally widespread and regionally restricted MTBC lineages in The Gambia and reveal a substantial burden of resistance-associated mutations of uncertain significance in the WHO catalogue. Sustained genomic surveillance and region-specific interpretation of resistance mutations are essential to support End TB strategies in high-burden settings.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-42003-2","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T09:46:02Z","timestamp":1772617562000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genome-wide analyses of Mycobacterium tuberculosis complex isolates reveal insights into circulating lineages and drug resistance mutations in The Gambia"],"prefix":"10.1038","volume":"16","author":[{"given":"Fatou","family":"Faal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naffie","family":"Top","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olimatou","family":"Jobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang M.","family":"Colley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Ayorinde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alieu","family":"Mendy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binta","family":"Sarr-Kuyateh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Donkor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Antonio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouke C.","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Rachow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Kampmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayne S.","family":"Sutherland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom L.","family":"Blundell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Campino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kohl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Dreyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Neimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun P.","family":"Pandurangan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taane G.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody E.","family":"Phelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopold D.","family":"Tientcheu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"42003_CR1","volume-title":"Global tuberculosis report 2023","author":"World Health, O","year":"2023","unstructured":"World Health, O. 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