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Here we show that <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> undergoes replicative aging (RA) that results from asymmetric cell division and causes phenotypic differences between mother and daughter cells similar to other pathogenic yeasts. Importantly, older <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> cells (10 generations) exhibited higher tolerance to fluconazole (FLC), micafungin, 5- flucytosine and amphotericin B compared to younger (0\u20133 generation) cells. Increased FLC tolerance was associated with increased Rhodamine 6G (R6G) efflux and therapeutic failure of FLC in a <jats:italic>Galleria<\/jats:italic> infection model. The higher efflux in the older cells correlated with overexpression of the efflux pump encoding gene <jats:italic>CDR1<\/jats:italic> (4-fold). In addition, 8-fold upregulation of the azole target encoding gene <jats:italic>ERG11<\/jats:italic> was noted in the older cells. Analysis of genomic DNA from older cells by qPCR indicates that transient gene duplication of <jats:italic>CDR1<\/jats:italic> and <jats:italic>ERG11<\/jats:italic> causes the observed age-dependent enhanced FLC tolerance in <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> strains. Furthermore, older cells exhibited a thickened cell wall, decreased neutrophil killing (24% vs 50%), increased epithelial cell adhesion (31.6% vs 17.8%) and upregulation of adhesin protein Als5p. Thus, this study demonstrates that transient gene duplication can occur during RA, causing increased FLC tolerance in old <jats:italic>C<\/jats:italic>. <jats:italic>auris<\/jats:italic> cells.<\/jats:p>","DOI":"10.1038\/s41598-019-41513-6","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T11:03:11Z","timestamp":1553511791000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Gene Duplication Associated with Increased Fluconazole Tolerance in Candida auris cells of Advanced Generational Age"],"prefix":"10.1038","volume":"9","author":[{"given":"Somanon","family":"Bhattacharya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Holowka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-7298","authenticated-orcid":false,"given":"Erika P.","family":"Orner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6847-5518","authenticated-orcid":false,"given":"Bettina C.","family":"Fries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,25]]},"reference":[{"key":"41513_CR1","doi-asserted-by":"publisher","first-page":"e1006290","DOI":"10.1371\/journal.ppat.1006290","volume":"13","author":"A Chowdhary","year":"2017","unstructured":"Chowdhary, A., Sharma, C. & Meis, J. 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