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Because aneuploidy simultaneously affects many genes, it has the potential to confer multiple phenotypes to the same cells. Here, we analyzed the mechanisms by which Candida albicans, the most prevalent human fungal pathogen, acquires the ability to survive both chemotherapeutic agents and antifungal drugs. Strikingly, adaptation to both types of drugs was accompanied by the acquisition of specific whole-chromosome aneuploidies, with some aneuploid karyotypes recovered independently and repeatedly from very different drug conditions. Specifically, strains selected for survival in hydroxyurea, an anticancer drug, acquired cross-adaptation to caspofungin, a first-line antifungal drug, and both acquired traits were attributable to trisomy of the same chromosome: loss of trisomy was accompanied by loss of adaptation to both drugs. Mechanistically, aneuploidy simultaneously altered the copy number of most genes on chromosome 2, yet survival in hydroxyurea or caspofungin required different genes and stress response pathways. Similarly, chromosome 5 monosomy conferred increased tolerance to both fluconazole and to caspofungin, antifungals with different mechanisms of action. Thus, the potential for cross-adaptation is not a feature of aneuploidy per se; rather, it is dependent on specific genes harbored on given aneuploid chromosomes. Furthermore, pre-exposure to hydroxyurea increased the frequency of appearance of caspofungin survivors, and hydroxyurea-adapted C. albicans cells were refractory to antifungal drug treatment in a mouse model of systemic candidiasis. This highlights the potential clinical consequences for the management of cancer chemotherapy patients at risk of fungal infections.<\/jats:p>","DOI":"10.1093\/molbev\/msz104","type":"journal-article","created":{"date-parts":[[2019,4,20]],"date-time":"2019-04-20T03:07:01Z","timestamp":1555729621000},"page":"1768-1782","source":"Crossref","is-referenced-by-count":110,"title":["Aneuploidy Enables Cross-Adaptation to Unrelated Drugs"],"prefix":"10.1093","volume":"36","author":[{"given":"Feng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Biotechnology, School of Molecular Cell Biology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Teoh","sequence":"additional","affiliation":[{"name":"Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alrina Shin Min","family":"Tan","sequence":"additional","affiliation":[{"name":"Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongbing","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China"},{"name":"Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Pavelka","sequence":"additional","affiliation":[{"name":"Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8577-0084","authenticated-orcid":false,"given":"Judith","family":"Berman","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Biotechnology, School of Molecular Cell Biology and Biotechnology, The George S. 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