Broad Institute of MIT and Harvard, Cambridge, United States
Reeta P Rao
Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, United States
Judith Berman
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States; Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel
Dawn A Thompson
Broad Institute of MIT and Harvard, Cambridge, United States
Aviv Regev
Department of Biology, Broad Institute of MIT and Harvard, Cambridge, United States; Broad Institute of MIT and Harvard, Cambridge, United States; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States
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.
