title: The evolution of drug resistance in clinical isolates of Candida albicans.
abstract: Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.
authors: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Christopher B
authors: CB
authors: Ford
authors: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Jason M
authors: JM
authors: Funt
authors: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States.
authors: Darren
authors: D
authors: Abbey
authors: Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, United States.
authors: Luca
authors: L
authors: Issi
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Candace
authors: C
authors: Guiducci
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Diego A
authors: DA
authors: Martinez
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Toni
authors: T
authors: Delorey
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Bi Yu
authors: BY
authors: Li
authors: School of Biological Sciences, University of Missouri at Kansas City, Kansas City, United States.
authors: Theodore C
authors: TC
authors: White
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Christina
authors: C
authors: Cuomo
authors: Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, United States.
authors: Reeta P
authors: RP
authors: Rao
authors: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States.
authors: Judith
authors: J
authors: Berman
authors: Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Dawn A
authors: DA
authors: Thompson
authors: Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States.
authors: Aviv
authors: A
authors: Regev
mesh_terms: D000268:Adhesiveness; D000782:Aneuploidy; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology*; D025141:Drug Resistance, Fungal / Q000187:drug effects* / Q000235:genetics*; D019143:Evolution, Molecular; D015725:Fluconazole / Q000494:pharmacology; D056084:Genetic Fitness / Q000187:drug effects; D015894:Genome, Human; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D014774:Virulence / Q000187:drug effects / Q000235:genetics
chemical_list: D015725:Fluconazole
keywords: Candida albicans; drug resistance; evolution; evolutionary biology; genomics; infectious disease; microbiology; virulence
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