title: α-amanitin resistance in Drosophila melanogaster: A genome-wide association approach.
abstract: We investigated the mechanisms of mushroom toxin resistance in the Drosophila Genetic Reference Panel (DGRP) fly lines, using genome-wide association studies (GWAS). While Drosophila melanogaster avoids mushrooms in nature, some lines are surprisingly resistant to α-amanitin-a toxin found solely in mushrooms. This resistance may represent a pre-adaptation, which might enable this species to invade the mushroom niche in the future. Although our previous microarray study had strongly suggested that pesticide-metabolizing detoxification genes confer α-amanitin resistance in a Taiwanese D. melanogaster line Ama-KTT, none of the traditional detoxification genes were among the top candidate genes resulting from the GWAS in the current study. Instead, we identified Megalin, Tequila, and widerborst as candidate genes underlying the α-amanitin resistance phenotype in the North American DGRP lines, all three of which are connected to the Target of Rapamycin (TOR) pathway. Both widerborst and Tequila are upstream regulators of TOR, and TOR is a key regulator of autophagy and Megalin-mediated endocytosis. We suggest that endocytosis and autophagy of α-amanitin, followed by lysosomal degradation of the toxin, is one of the mechanisms that confer α-amanitin resistance in the DGRP lines.
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Mitchell
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Catrina E
authors.initials: CE
authors.lastname: Latuszek
authors.affiliation: Department of Neurology, University of Wisconsin School of Medicine and Public Health, 1300 University Ave., Madison, WI, United States of America.
authors.forename: Kara R
authors.initials: KR
authors.lastname: Vogel
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Greenlund
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Hobmeier
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Olivia K
authors.initials: OK
authors.lastname: Ingram
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Dufek
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Pecore
authors.affiliation: College of Human Medicine, Michigan State University, Clinical Center, East Lansing, MI, United States of America.
authors.forename: Felicia R
authors.initials: FR
authors.lastname: Nip
authors.affiliation: U.S. Forest Service, Salt Lake Ranger District 6944 S, 3000 E, Salt Lake City, UT, United States of America.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Johnson
authors.affiliation: School of Forest Resources and Environmental Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ji
authors.affiliation: School of Forest Resources and Environmental Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Hairong
authors.initials: H
authors.lastname: Wei
authors.affiliation: School of Forest Resources and Environmental Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gailing
authors.affiliation: Department of Biological Sciences, Michigan Technological University, 1400 Townsend Dr., Houghton, MI, United States of America.
authors.forename: Thomas
authors.identifier: http://orcid.org/0000-0002-8865-365X
authors.initials: T
authors.lastname: Werner
mesh_terms: D053959:Alpha-Amanitin / Q000494:pharmacology*; D000818:Animals; D003433:Crosses, Genetic; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics*; D004351:Drug Resistance; D004705:Endocytosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D014644:Genetic Variation; D007814:Larva / Q000187:drug effects; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010575:Pesticides / Q000737:chemistry; D010641:Phenotype; D012313:RNA / Q000032:analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013624:Taiwan
chemical_list: D053959:Alpha-Amanitin; D029721:Drosophila Proteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010575:Pesticides; D012313:RNA; D058570:TOR Serine-Threonine Kinases