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In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS) to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM). Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.<\/jats:p>","DOI":"10.1534\/g3.116.037499","type":"journal-article","created":{"date-parts":[[2017,2,10]],"date-time":"2017-02-10T21:20:26Z","timestamp":1486761626000},"page":"1165-1176","source":"Crossref","is-referenced-by-count":108,"title":["A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection"],"prefix":"10.1093","volume":"7","author":[{"given":"Johanna","family":"Rhodes","sequence":"first","affiliation":[{"name":"Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew A","family":"Beale","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Faculty of Medical Sciences, University College London, WC1E 6BT United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Vanhove","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph N","family":"Jarvis","sequence":"additional","affiliation":[{"name":"Botswana-UPenn Partnership, 0022 Gaborone, Botswana"},{"name":"Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104"},{"name":"Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, WC1E 7HT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichina","family":"Kannambath","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St. George\u2019s University London, SW17 0RE United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Simpson","sequence":"additional","affiliation":[{"name":"National Health Laboratory Service, Greenpoint, Cape Town, 8005 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthea","family":"Ryan","sequence":"additional","affiliation":[{"name":"National Health Laboratory Service, Greenpoint, Cape Town, 8005 South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Meintjes","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cape Town, 7925, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S","family":"Harrison","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St. George\u2019s University London, SW17 0RE United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihana","family":"Bicanic","sequence":"additional","affiliation":[{"name":"Institute of Infection and Immunity, St. George\u2019s University London, SW17 0RE United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,4,1]]},"reference":[{"issue":"3","key":"2021042013193981700_bib1","doi-asserted-by":"crossref","first-page":"e00536","DOI":"10.1128\/mBio.00536-15","article-title":"Genomic context of azole resistance mutations in aspergillus fumigatus determined using whole-genome sequencing.","volume":"6","author":"Abdolrasouli","year":"2015","journal-title":"MBio"},{"issue":"3","key":"2021042013193981700_bib2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s12281-012-0100-3","article-title":"EUCAST and CLSI: how to assess in vitro susceptibility and clinical resistance.","volume":"6","author":"Alastruey-Izquierdo","year":"2012","journal-title":"Curr. 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