Program Book - 27th Fungal Genetics Conference

CONCURRENT SESSION ABSTRACTSThe mutational landscape of gradual acquisition of drug resistance in clinical isolates of Candida albicans. Jason Funt 1 , Darren Abbey 7 , Luca Issi 5 , BrianOliver 3 , Theodore White 4 , Reeta Rao 5 , Judith Berman 6 , Dawn Thompson 1 , Aviv Regev 1,2 . 1) Broad Institute of MIT and Harvard, 7 Cambridge Center,Cambridge, MA 02142; 2) Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Masscahusetts Ave,Camridge, MA 02140; 3) Seattle Biomedical Research Institute, Seattle, WA; 4) School of Biological Sciences, University of Missouri at Kansas City, MS; 5)Worcester Polytechnic Institute, Department of Biology and Biotechnology, 100 Institute Road, Worcester MA 01609; 6) Tel Aviv University, Ramat Aviv,69978 Israel; 7) University of Minnesota, Minneapolis MN 55455 USA.Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals1. Infections are mostcommonly treated with azole inhibitors of ergosterol biosynthesis. Prophylactic treatment in immuncompromised patients2,3 often leads to thedevelopment of drug resistance. Since C. albicans is diploid and lacks a complete sexual cycle, conventional genetic analysis is challenging. An alternativeapproach is to study the mutations that arise naturally during the evolution of drug resistance in vivo, using isolates sampled consecutively from the samepatient. Studies in evolved isolates have implicated multiple mechanisms in drug resistance, but have focused on large-scale aberrations or candidategenes, and do not comprehensively chart the genetic basis of adaptation5. Here, we leveraged next-generation sequencing to systematically analyze 43isolates from 11 oral candidiasis patients, collected sequentially at two to 16 time points per patient. Because most isolates from an individual patientwere clonal, we could detect newly acquired mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss ofheterozygosity (LOH) events. Focusing on new mutations that were both persistent within a patient and recurrent across patients, we found that LOHevents were commonly associated with acquired resistance, and that persistent and recurrent point mutations in over 150 genes may be related to thecomplex process of adaptation to the host. Conversely, most aneuploidies were transient and did not directly correlate with changes in drug resistance.Our work sheds new light on the molecular mechanisms underlying the evolution of drug resistance and host adaptation.27th Fungal Genetics Conference | 57