{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:15:12Z","timestamp":1787224512888,"version":"build-2736575974"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:p>Tuberculosis (TB) control programs use whole-genome sequencing (WGS) of <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) for detecting and investigating TB case clusters. Existence of few genomic differences between <jats:italic>Mtb<\/jats:italic> isolates might indicate TB cases are the result of recent transmission. However, the variable and sometimes long duration of latent infection, combined with uncertainty in the <jats:italic>Mtb<\/jats:italic> mutation rate during latency, can complicate interpretation of WGS results. To estimate the association between infection duration and single nucleotide polymorphism (SNP) accumulation in the <jats:italic>Mtb<\/jats:italic> genome, we first analyzed pairwise SNP differences among TB cases from Los Angeles County, California, with strong epidemiologic links. We found that SNP distance alone was insufficient for concluding that cases are linked through recent transmission. Second, we describe a well-characterized cluster of TB cases in California to illustrate the role of genomic data in conclusions regarding recent transmission. Longer presumed latent periods were inconsistently associated with larger SNP differences. Our analyses suggest that WGS alone cannot be used to definitively determine that a case is attributable to recent transmission. Methods for integrating clinical, epidemiologic, and genomic data can guide conclusions regarding the likelihood of recent transmission, providing local public health practitioners with better tools for monitoring and investigating TB transmission.<\/jats:p>","DOI":"10.3389\/fpubh.2021.790544","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T05:50:58Z","timestamp":1642053058000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Mutation of Mycobacterium tuberculosis and Implications for Using Whole-Genome Sequencing for Investigating Recent Tuberculosis Transmission"],"prefix":"10.3389","volume":"9","author":[{"given":"Kristin N.","family":"Nelson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Talarico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shameer","family":"Poonja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clinton J.","family":"McDaniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Cilnis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia H.","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kala","family":"Raz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy S.","family":"Noboa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Cowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tambi","family":"Shaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Posey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Silk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"B1","volume-title":"Prioritizing Tuberculosis Genotype Clusters for Further Investigation and Public Health Action","year":"2017"},{"key":"B2","volume-title":"Reported Tuberculosis in the United States, 2019","year":"2019"},{"key":"B3","volume-title":"Whole-Genome Sequencing for Investigation of Recent TB Transmission in the United States: Current Uses and Future Plans.","author":"Talarico","year":""},{"key":"B4","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/ng.811","article-title":"Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection","volume":"43","author":"Ford","year":"2011","journal-title":"Nat Genet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e05166","DOI":"10.7554\/eLife.05166","article-title":"Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area","volume":"4","author":"Guerra-Assun\u00e7\u00e3o","year":"2015","journal-title":"eLife"},{"key":"B6","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1093\/infdis\/jix298","article-title":"Genomic epidemiology of a major mycobacterium tuberculosis outbreak: retrospective cohort study in a low-incidence setting using sparse time-series sampling","volume":"216","author":"Folkvardsen","year":"2017","journal-title":"J Infect Dis"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1001387","DOI":"10.1371\/journal.pmed.1001387","article-title":"Whole genome sequencing versus traditional genotyping for investigation of a Mycobacterium tuberculosis outbreak: a longitudinal molecular epidemiological study","volume":"10","author":"Roetzer","year":"2013","journal-title":"PLoS Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/S1473-3099(12)70277-3","article-title":"Whole-genome sequencing to delineate Mycobacterium tuberculosis outbreaks: a retrospective observational study","volume":"13","author":"Walker","year":"2013","journal-title":"Lancet Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e0132840","DOI":"10.1371\/journal.pone.0132840","article-title":"Whole genome sequencing shows a low proportion of tuberculosis disease is attributable to known close contacts in rural Malawi","volume":"10","author":"Glynn","year":"2015","journal-title":"PLoS ONE"},{"key":"B10","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S1473-3099(16)30418-2","article-title":"Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation","volume":"17","author":"Yang","year":"2017","journal-title":"Lancet Inf Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/S2213-2600(14)70027-X","article-title":"Assessment of Mycobacterium tuberculosis transmission in Oxfordshire, UK, 2007\u201312, with whole pathogen genome sequences: an observational study","volume":"2","author":"Walker","year":"2014","journal-title":"Lancet Respir Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/1471-2334-13-110","article-title":"Inferring patient to patient transmission of Mycobacterium tuberculosis from whole genome sequencing data","volume":"13","author":"Bryant","year":"2013","journal-title":"BMC Infect Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"104184","DOI":"10.1016\/j.meegid.2020.104184","article-title":"Investigation of a rapidly spreading tuberculosis outbreak using whole-genome sequencing","volume":"81","author":"Comin","year":"2020","journal-title":"Infect Genet Evol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1093\/infdis\/jiu601","article-title":"Tracking a tuberculosis outbreak over 21 years: strain-specific single-nucleotide polymorphism typing combined with targeted whole-genome sequencing","volume":"211","author":"Stucki","year":"2015","journal-title":"J Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1128\/jcm.35.4.907-914.1997","article-title":"Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology","volume":"35","author":"Kamerbeek","year":"1997","journal-title":"J Clin Microbiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4498","DOI":"10.1128\/JCM.01392-06","article-title":"Proposal for standardization of optimized mycobacterial interspersed repetitive unit-variable-number tandem repeat typing of Mycobacterium tuberculosis","volume":"44","author":"Supply","year":"2006","journal-title":"J Clin Microbiol"},{"key":"B17","volume-title":"Guidelines for the Investigation of Contacts of Persons With Infectious Tuberculosis: Recommendations from the National Tuberculosis Controllers Association and CDC","author":"Taylor","year":"2005"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1086\/378240","article-title":"Stability of DNA patterns and evidence of Mycobacterium tuberculosis reactivation occurring decades after the initial infection","volume":"188","author":"Lillebaek","year":"2003","journal-title":"J Infect Dis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/j.ijmm.2016.05.017","article-title":"Substantial molecular evolution and mutation rates in prolonged latent Mycobacterium tuberculosis infection in humans","volume":"306","author":"Lillebaek","year":"2016","journal-title":"Int J Med Microbiol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/j.meegid.2011.02.002","article-title":"How dormant is Mycobacterium tuberculosis during latency? A study integrating genomics and molecular epidemiology","volume":"11","author":"Yang","year":"2011","journal-title":"Infect Genet Evol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e91024","DOI":"10.1371\/journal.pone.0091024","article-title":"Whole genome sequencing of Mycobacterium tuberculosis reveals slow growth and low mutation rates during latent infections in humans","volume":"9","author":"Colangeli","year":"2014","journal-title":"PLoS ONE"},{"key":"B22","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/nm.1915","article-title":"A replication clock for Mycobacterium tuberculosis","volume":"15","author":"Gill","year":"2009","journal-title":"Nat Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1038\/ng.2656","article-title":"Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis","volume":"45","author":"Ford","year":"2013","journal-title":"Nat Genet"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1056\/NEJMsr1813907","article-title":"Pathogen genomics in public health","volume":"381","author":"Armstrong","year":"2019","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1702313","DOI":"10.1183\/13993003.02313-2017","article-title":"The use of whole-genome sequencing in cluster investigation of a multidrug-resistant tuberculosis outbreak","volume":"51","author":"Lalor","year":"2018","journal-title":"Eur Respir J"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e188","DOI":"10.1017\/S0950268819000670","article-title":"Whole genome sequencing for improved understanding of Mycobacterium tuberculosis transmission in a remote circumpolar region","volume":"147","author":"Guthrie","year":"2019","journal-title":"Epidemiol Infect"},{"key":"B27","doi-asserted-by":"publisher","first-page":"667337","DOI":"10.3389\/fpubh.2021.667337","article-title":"Logically Inferred Tuberculosis Transmission (LITT): a data integration algorithm to rank potential source cases","volume":"9","author":"Winglee","year":"2021","journal-title":"Front Public Health"},{"key":"B28","doi-asserted-by":"publisher","first-page":"257","DOI":"10.15585\/mmwr.mm6811a2","article-title":"Tuberculosis \u2013 United States, 2018","volume":"68","author":"Talwar","year":"2019","journal-title":"Morb Mortal Wkly Rep"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0153728","DOI":"10.1371\/journal.pone.0153728","article-title":"Recent transmission of tuberculosis \u2014 United States, 2011\u20132014","volume":"11","author":"Yuen","year":"2016","journal-title":"PLoS ONE"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1093\/aje\/kwx182","article-title":"Shared genomic variants: identification of transmission routes using pathogen deep-sequence data","volume":"186","author":"Worby","year":"2017","journal-title":"Am J Epidemiol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1016\/j.cmi.2019.03.022","article-title":"Role and value of whole genome sequencing in studying tuberculosis transmission","volume":"25","author":"Nikolayevskyy","year":"2019","journal-title":"Clinl Microbiol Infect"},{"key":"B32","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.ebiom.2019.08.010","article-title":"Direct transmission of within-host Mycobacterium tuberculosis diversity to secondary cases can lead to variable between-host heterogeneity without de novo mutation: a genomic investigation","volume":"47","author":"S\u00e9raphin","year":"2019","journal-title":"EBioMedicine"},{"key":"B33","first-page":"992","article-title":"Patient and health care system delays in pulmonary tuberculosis diagnosis in a low-incidence state","volume":"9","author":"Golub","year":"2005","journal-title":"Int J Tuberc Lung Dis"},{"key":"B34","doi-asserted-by":"publisher","first-page":"306","DOI":"10.7554\/eLife.16644","article-title":"Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis","volume":"5","author":"Eldholm","year":"2016","journal-title":"Trends Ecol Evol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"k2738","DOI":"10.1136\/bmj.k2738","article-title":"Revisiting the timetable of tuberculosis","volume":"362","author":"Behr","year":"2018","journal-title":"BMJ"}],"container-title":["Frontiers in Public Health"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2021.790544\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T05:51:06Z","timestamp":1642053066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpubh.2021.790544\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":35,"alternative-id":["10.3389\/fpubh.2021.790544"],"URL":"https:\/\/doi.org\/10.3389\/fpubh.2021.790544","relation":{},"ISSN":["2296-2565"],"issn-type":[{"value":"2296-2565","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]},"article-number":"790544"}}