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We identified PPE50 as a novel subfamily of PE\/PPE proteins comprising eight variants. Surveying 387\u2009<jats:italic>M. tuberculosis<\/jats:italic> complex (MTBC) strains representing global phylogeography, we found PPE50 variants are lineage-specific and stably associated with geographic regions, defining them as phylogeographically-associated proteins (PAPs). PPE50-381 is the ancestral variant (present in early-branching <jats:italic>M. canettii<\/jats:italic>) and the only variant observed in both Ancient and Modern MTBC lineages. Transcriptomic analysis confirmed that <jats:italic>ppe50<\/jats:italic> variant genes are expressed in strains from respective MTBC lineages, but not in all L1 strains and sub-lineages L2.1 and L4.1\u00a0where the gene was deleted. In silico analysis revealed significant structural diversity among variants, particularly in C-terminal regions. This strong association of <jats:italic>M. tuberculosis<\/jats:italic> protein diversity with phylogeography suggests PPE50 may contribute to MTBC adaptation to different host populations. Further characterization of PPE50 and other PAPs may facilitate improved targeted\u00a0diagnostics, therapeutics and vaccines.<\/jats:p>","DOI":"10.1038\/s42003-025-08383-3","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T08:49:19Z","timestamp":1752137359000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PPE50 variants as novel phylogeographic signatures of host-pathogen co-evolution in tuberculosis"],"prefix":"10.1038","volume":"8","author":[{"given":"Christopher","family":"D\u2019Souza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8323-7019","authenticated-orcid":false,"given":"Jody E.","family":"Phelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3670-8786","authenticated-orcid":false,"given":"Paula-Josefina","family":"Gomez-Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Thorpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8985-9265","authenticated-orcid":false,"given":"Taane G.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1940-3144","authenticated-orcid":false,"given":"Anthony G.","family":"Tsolaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"8383_CR1","unstructured":"WHO Global Tuberculosis Report. 2023; Available from: https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports\/global-tuberculosis-report-2023."},{"key":"8383_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/imr.12264","volume":"264","author":"D Brites","year":"2015","unstructured":"Brites, D. & Gagneux, S. 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