CURRENT ISSUE (/CONTENT/CURRENT) ARCHIVE (/CONTENT) NEWS & MULTIMEDIA (/MULTIMEDIA) AUTHORS (/SITE/AUTHORS/INDEX.XHTML) ABOUT (/SITE/ABOUTPNAS/INDEX.XHTML) COLLECTED ARTICLES (/SITE/MISC/COLLECTEDPAPERS.XHTML) BROWSE BY TOPIC (/SEARCH) EARLY EDITION (/CONTENT/EARLY/RECENT) FRONT MATTER (HTTP://FRONTMATTER.PNAS.ORG) Proceedings of the National Academy of Sciences This Issue www.pnas.org (/) > Current Issue (/content/113/48.toc) > vol. 113 no. 48 > Vegard Eldholm, 13881–13886, doi: 10.1073/pnas.1611283113 Armed con爿ict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis a,1 Vegard Eldholm (/search?author1=Vegard+Eldholm&sortspec=date&submit=Submit) , a (/content/113/48.toc) John H.­O. Pettersson (/search?author1=John+H.­O.+Pettersson&sortspec=date&submit=Submit) , November 29, a Ola B. Brynildsrud (/search?author1=Ola+B.+Brynildsrud&sortspec=date&submit=Submit) , 2016 b vol. 113 no. 48 Andrew Kitchen (/search?author1=Andrew+Kitchen&sortspec=date&submit=Submit) , Masthead (PDF) c (/content/113/48/local/masthead.pdf) Erik Michael Rasmussen (/search?author1=Erik+Michael+Rasmussen&sortspec=date&submit=Submit) , Table of Contents c Troels Lillebaek (/search?author1=Troels+Lillebaek&sortspec=date&submit=Submit) , (/content/113/48.toc) a Janne O. Rønning (/search?author1=Janne+O.+R%C3%B8nning&sortspec=date&submit=Submit) , d Valeriu Crudu (/search?author1=Valeriu+Crudu&sortspec=date&submit=Submit) , PREV ARTICLE NEXT ARTICLE (/CONTENT/113/48/1(3/C87O5N.STEHNOTR/T1)13/48/13887.SHORT) a Anne Torunn Mengshoel (/search?author1=Anne+Torunn+Mengshoel&sortspec=date&submit=Submit) , a Nadia Debech (/search?author1=Nadia+Debech&sortspec=date&submit=Submit) , a Kristian Alfsnes (/search?author1=Kristian+Alfsnes&sortspec=date&submit=Submit) , Don't Miss a Jon Bohlin (/search?author1=Jon+Bohlin&sortspec=date&submit=Submit) , e,f Caitlin S. Pepperell (/search?author1=Caitlin+S.+Pepperell&sortspec=date&submit=Submit) , and g Francois Balloux (/search?author1=Francois+Balloux&sortspec=date&submit=Submit) (https://play.google.com/store/apps/details? Author Affiliations id=org.highwire.fta.android.app.pnas1&hl=en) PNAS Full-Text Edited by Richard E. Lenski, Michigan State University, East Lansing, MI, and approved October 20, 2016 (received for review Android App (https://play.google.com/store/apps/details? July 12, 2016) id=org.highwire.fta.android.app.pnas1&hl=en) Download the app Abstract (/content/113/48/13881.abstract) Full Text Authors & Info for free from Google Play today! Figures (/content/113/48/13881.Hgures-only) SI (/content/113/48/13881/suppl/DCSupplemental) Metrics Related Content PDF (/content/113/48/13881.full.pdf) Navigate This Article PDF + SI (/content/113/48/13881.full.pdf?with-ds=yes) Top SigniHcance Abstract We used population genomic analyses to reconstruct the recent history and dispersal of a major Results and Discussion clade of Mycobacterium tuberculosis in central Asia and beyond. Our results indicate that the fall of the Soviet Union and the ensuing collapse of public health systems led to a rise in M. tuberculosis Materials and Methods drug resistance. We also show that armed conflict and population displacement is likely to have SI Materials and Methods aided the export of this clade from central Asia to war­torn Afghanistan and beyond. Acknowledgments Footnotes Abstract The “Beijing” Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been References associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has Article Tools recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan Article Alerts during the 1979–1989 Soviet–Afghan war and spread further after population displacement in the wake of Export Citation the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale Save for Later in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not © Request Permission (/site/aboutpnas/rightperm.xhtml) observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time. Share Mycobacterium tuberculosis (/search?fulltext=Mycobacterium+tuberculosis&sortspec=date&submit=Submit&andorexac (t/feuxlltexrtn=aplh-rreafs?e) evolution (/search?fulltext=evolution&sortspec=date&submit=Submit&andorexactfulltext=phrase) tag_url=http://www.pnas.org/cgi/content/short/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=FACEBOOK) antimicrobial resistance (/search?fulltext=antimicrobial+resistance&sortspec=date&submit=Submit&andorexactfulltext=phrase) phylodynamic analysis (/search?fulltext=phylodynamic+analysis&sortspec=date&submit=Submit&andorexactfulltext=phr a(/seex)ternal-ref? tip­dating (/search?fulltext=tip­dating&sortspec=date&submit=Submit&andorexactfulltext=phrase) tag_url=http://www.pnas.org/cgi/content/long/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=TWITTER) The Mycobacterium tuberculosis complex (MTBC) comprises seven main lineages. Of these, lineages 2, 3, and 4 are found across most of the globe, but their regional distribution varies and reflects historical and (/external-ref? recent human population movements. L2 (“L2” and “Beijing lineage” are used interchangeably throughout tag_url=http://www.pnas.org/cgi/content/long/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- the text) has a southeast Asian (1) or east Asian (2) origin and has received considerable attention as it is -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=CITEULIKE) spreading globally (3), may be associated with accelerated progression of disease (4, 5), and is associated (/external-ref? with increased antibiotic resistance (5). It also has been suggested that L2 exhibits an elevated mutation tag_url=http://www.pnas.org/cgi/content/long/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- rate relative to other M. tuberculosis (Mtb) lineages, but studies have yielded differing results in this regard -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=DEL_ICIO_US) (6, 7). (/external-ref? There is no consensus in the literature regarding the age of the MTBC and its main lineages, and different tag_url=http://www.pnas.org/cgi/content/long/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- studies have approached this question using distinct strategies. One such approach, the “out of Africa” -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=DIGG) hypothesis, is based on the assumption of codivergence of Mtb with its human host (1, 8), and suggests (/external-ref? that the most recent common ancestor (MRCA) of extant Mtb existed roughly 40,000–70,000 y ago, with the tag_url=http://www.pnas.org/cgi/content/short/113/48/13881&title=Armed%20con爿ict%20and%20population%20displacement%20as%20drivers%20of%20the%20evolution%20and%20dispersal%20of%20Mycobacterium%20tuberculosis+- bacillus subsequently spreading globally with human migrations out of Africa (9, 10). In contrast, the two -+Eldholm%20et%20al.%20113%20%2848%29%3A%2013881+--+PNAS&doi=10.1073/pnas.1611283113&link_type=MENDELEY) studies that relied on genomic sequence data using ancient DNA (aDNA) analysis point to a 10­fold younger origin, around 6,000 y ago (11, 12). Even though calibration with aDNA is becoming the gold standard for Published online before print November 21, 2016, doi: dating evolutionary events, few noncontemporaneous MTBC genomes are available at present. One 10.1073/pnas.1611283113 previous study relied on ∼1,000­y­old M. pinnipedii isolates, an animal­associated MTBC strain (11). A PNAS (Proceedings of the National second study relied on Mtb sensu stricto genomes for calibration, but the isolates were only 200–250 y old Academy of Sciences) November 29, 2016 vol. 113 no. 48 13881- (12). These two studies yielded similar rate estimates, despite including data from very different time 13886 periods. The substitution rate estimates of ∼5 × 10−8 substitutions/site/year (s/s/y) obtained in these aDNA ClassiHcations studies are slightly lower than estimates from epidemiologic studies and other studies based on −7 −7 Biological Sciences contemporaneous sampling, all of which produced rate estimates around 0.7 × 10 – 1.3 × 10 s/s/y, Microbiology (/search?