title: In the hunt for genomic markers of metabolic resistance to pyrethroids in the mosquito Aedes aegypti: An integrated next-generation sequencing approach.
abstract: The capacity of Aedes mosquitoes to resist chemical insecticides threatens the control of major arbovirus diseases worldwide. Until alternative control tools are widely deployed, monitoring insecticide resistance levels and identifying resistance mechanisms in field mosquito populations is crucial for implementing appropriate management strategies. Metabolic resistance to pyrethroids is common in Aedes aegypti but the monitoring of the dynamics of resistant alleles is impeded by the lack of robust genomic markers.
  
  
  
  In an attempt to identify the genomic bases of metabolic resistance to deltamethrin, multiple resistant and susceptible populations originating from various continents were compared using both RNA-seq and a targeted DNA-seq approach focused on the upstream regions of detoxification genes. Multiple detoxification enzymes were over transcribed in resistant populations, frequently associated with an increase in their gene copy number. Targeted sequencing identified potential promoter variations associated with their over transcription. Non-synonymous variations affecting detoxification enzymes were also identified in resistant populations.
  
  
  
  This study not only confirmed the role of gene copy number variations as a frequent cause of the over expression of detoxification enzymes associated with insecticide resistance in Aedes aegypti but also identified novel genomic resistance markers potentially associated with their cis-regulation and modifications of their protein structure conformation. As for gene transcription data, polymorphism patterns were frequently conserved within regions but differed among continents confirming the selection of different resistance factors worldwide. Overall, this study paves the way of the identification of a comprehensive set of genomic markers for monitoring the spatio-temporal dynamics of the variety of insecticide resistance mechanisms in Aedes aegypti.
authors.affiliation: Laboratoire d'Ecologie Alpine (LECA), CNRS, UMR 5553, 2233 rue de la piscine Grenoble, France.|Université Grenoble-Alpes, France.|Environmental and Systems Biology (BEeSy), Université Grenoble Alpes, Grenoble, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Faucon
authors.affiliation: Laboratoire d'Ecologie Alpine (LECA), CNRS, UMR 5553, 2233 rue de la piscine Grenoble, France.|Université Grenoble-Alpes, France.|Environmental and Systems Biology (BEeSy), Université Grenoble Alpes, Grenoble, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gaude
authors.affiliation: Unité d'Entomologie Médicale, Institut Pasteur de la Guyane, 23 avenue Pasteur, Cayenne, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusfour
authors.affiliation: Pôle Rhône Alpes de Bioinformatique, Université Lyon 1, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navratil
authors.affiliation: Institut de Recherche pour le Développement (IRD), Maladies Infectieuses et Vecteurs, Ecologie, Génétique, Evolution et Contrôle (IRD 224-CNRS 5290 UM1-UM2), Montpellier, France.|Department of Entomology, Faculty of Agriculture, Kasetsart University, Lat Yao Chatuchak Bangkok, Thailand.
authors.forename: Vincent
authors.initials: V
authors.lastname: Corbel
authors.affiliation: Department of Entomology, Faculty of Agriculture, Kasetsart University, Lat Yao Chatuchak Bangkok, Thailand.|Center for Advanced Studies for Agriculture and Food, Kasetsart University Institute for Advanced Studies, Kasetsart University, Bangkok Thailand (CASAF, NRU-KU, Thailand).
authors.forename: Waraporn
authors.initials: W
authors.lastname: Juntarajumnong
authors.affiliation: Unité d'Entomologie Médicale, Institut Pasteur de la Guyane, 23 avenue Pasteur, Cayenne, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Girod
authors.affiliation: Institut für Populations genetik, Vetmeduni Vienna, Wien, Austria.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Poupardin
authors.affiliation: Laboratoire d'Ecologie Alpine (LECA), CNRS, UMR 5553, 2233 rue de la piscine Grenoble, France.|Université Grenoble-Alpes, France.|Environmental and Systems Biology (BEeSy), Université Grenoble Alpes, Grenoble, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Boyer
authors.affiliation: Laboratoire d'Ecologie Alpine (LECA), CNRS, UMR 5553, 2233 rue de la piscine Grenoble, France.|Université Grenoble-Alpes, France.|Environmental and Systems Biology (BEeSy), Université Grenoble Alpes, Grenoble, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Reynaud
authors.affiliation: Laboratoire d'Ecologie Alpine (LECA), CNRS, UMR 5553, 2233 rue de la piscine Grenoble, France.|Université Grenoble-Alpes, France.|Environmental and Systems Biology (BEeSy), Université Grenoble Alpes, Grenoble, France.
authors.forename: Jean-Philippe
authors.identifier: 0000-0002-3950-5909
authors.initials: JP
authors.lastname: David
mesh_terms: D000330:Aedes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D008658:Inactivation, Metabolic; D007305:Insecticide Resistance / Q000235:genetics*; D007306:Insecticides / Q000378:metabolism* / Q000494:pharmacology; D009570:Nitriles / Q000378:metabolism* / Q000494:pharmacology; D011722:Pyrethrins / Q000378:metabolism* / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: D005819:Genetic Markers; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017180:decamethrin