title: The ace-1 Locus Is Amplified in All Resistant Anopheles gambiae Mosquitoes: Fitness Consequences of Homogeneous and Heterogeneous Duplications.
abstract: Gene copy-number variations are widespread in natural populations, but investigating their phenotypic consequences requires contemporary duplications under selection. Such duplications have been found at the ace-1 locus (encoding the organophosphate and carbamate insecticides' target) in the mosquito Anopheles gambiae (the major malaria vector); recent studies have revealed their intriguing complexity, consistent with the involvement of various numbers and types (susceptible or resistant to insecticide) of copies. We used an integrative approach, from genome to phenotype level, to investigate the influence of duplication architecture and gene-dosage on mosquito fitness. We found that both heterogeneous (i.e., one susceptible and one resistant ace-1 copy) and homogeneous (i.e., identical resistant copies) duplications segregated in field populations. The number of copies in homogeneous duplications was variable and positively correlated with acetylcholinesterase activity and resistance level. Determining the genomic structure of the duplicated region revealed that, in both types of duplication, ace-1 and 11 other genes formed tandem 203kb amplicons. We developed a diagnostic test for duplications, which showed that ace-1 was amplified in all 173 resistant mosquitoes analyzed (field-collected in several African countries), in heterogeneous or homogeneous duplications. Each type was associated with different fitness trade-offs: heterogeneous duplications conferred an intermediate phenotype (lower resistance and fitness costs), whereas homogeneous duplications tended to increase both resistance and fitness cost, in a complex manner. The type of duplication selected seemed thus to depend on the intensity and distribution of selection pressures. This versatility of trade-offs available through gene duplication highlights the importance of large mutation events in adaptation to environmental variation. This impressive adaptability could have a major impact on vector control in Africa.
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.|Institut Régional de Santé Publique, Université d'Abomey Calavi, Cotonou, Benin.|Faculté des Sciences et Techniques, Laboratoire de Biologie et de Typage Moléculaire en Microbiologie, Université d'Abomey Calavi, Cotonou, Bénin.
authors.forename: Benoît S
authors.initials: BS
authors.lastname: Assogba
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Milesi
authors.affiliation: Institut Régional de Santé Publique, Université d'Abomey Calavi, Cotonou, Benin.
authors.forename: Luc S
authors.initials: LS
authors.lastname: Djogbénou
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Berthomieu
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Makoundou
authors.affiliation: Faculté des Sciences et Techniques, Laboratoire de Biologie et de Typage Moléculaire en Microbiologie, Université d'Abomey Calavi, Cotonou, Bénin.
authors.forename: Lamine S
authors.initials: LS
authors.lastname: Baba-Moussa
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Anna-Sophie
authors.initials: AS
authors.lastname: Fiston-Lavier
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Khalid
authors.initials: K
authors.lastname: Belkhir
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Labbé
authors.affiliation: Institut des Sciences de l'Evolution de Montpellier (UMR 5554, CNRS-UM-IRD-EPHE), Université de Montpellier, Place Eugène Bataillon, Montpellier, France.
authors.forename: Mylène
authors.initials: M
authors.lastname: Weill
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics*; D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D020440:Gene Duplication; D017344:Genes, Insect