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      Antifungal drug resistance evokedvia RNAi-dependent epimutations

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          Abstract

          Microorganisms evolve via mechanisms spanning sexual/parasexual reproduction, mutators, aneuploidy, Hsp90, and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidyl-prolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin 1 . Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth 2 . Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance (FK506 R) and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the FKBP12 fkbA gene, giving rise to drug-resistant epimutants. FK506 R epimutants readily reverted to the drug-sensitive wild-type (WT) phenotype when grown without drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNA (sRNA) and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves generation of a double-stranded RNA (dsRNA) trigger intermediate from the fkbA mature mRNA to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes.

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          Python for Scientific Computing

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            R: A Language and Environment for Statistical Computing.

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              An epigenetic mutation responsible for natural variation in floral symmetry.

              Although there have been many molecular studies of morphological mutants generated in the laboratory, it is unclear how these are related to mutants in natural populations, where the constraints of natural selection and breeding structure are quite different. Here we characterize a naturally occurring mutant of Linaria vulgaris, originally described more than 250 years ago by Linnaeus, in which the fundamental symmetry of the flower is changed from bilateral to radial. We show that the mutant carries a defect in Lcyc, a homologue of the cycloidea gene which controls dorsoventral asymmetry in Antirrhinum. The Lcyc gene is extensively methylated and transcriptionally silent in the mutant. This modification is heritable and co-segregates with the mutant phenotype. Occasionally the mutant reverts phenotypically during somatic development, correlating with demethylation of Lcyc and restoration of gene expression. It is surprising that the first natural morphological mutant to be characterized should trace to methylation, given the rarity of this mutational mechanism in the laboratory. This indicates that epigenetic mutations may play a more significant role in evolution than has hitherto been suspected.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                16 September 2014
                27 July 2014
                25 September 2014
                25 March 2015
                : 513
                : 7519
                : 555-558
                Affiliations
                [1 ]Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710
                [2 ]Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710
                [3 ]Bioinformatics Group, Duke Center for the Genomics of Microbial Systems, Duke University Medical Center, Durham, North Carolina 27710
                [4 ]High-Throughput Sequencing Facility, University of North Carolina, Chapel Hill, North Carolina 27599
                [5 ]Regional Campus of International Excellence “Campus Mare Nostrum”, Murcia 30100, Spain
                [6 ]Department of Genetics and Microbiology, Faculty of Biology, University of Murcia, Murcia 30100, Spain
                Author notes
                [* ]Corresponding author Room 322 CARL Building, Box 3546 Research Drive, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA, heitm001@ 123456duke.edu , Phone: (919) 684-2824, FAX: (919) 684-5458
                Article
                NIHMS605064
                10.1038/nature13575
                4177005
                25079329
                67659a5a-aa06-461d-b9e8-29a09afeac87
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