Dataset Information

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae.

ABSTRACT: While gene copy-number variations play major roles in long-term evolution, their early dynamics remains largely unknown. However, examples of their role in short-term adaptation are accumulating: identical repetitions of a locus (homogeneous duplications) can provide a quantitative advantage, while the association of differing alleles (heterogeneous duplications) allows carrying two functions simultaneously. Such duplications often result from rearrangements of sometimes relatively large chromosome fragments, and even when adaptive, they can be associated with deleterious side effects that should, however, be reduced by subsequent evolution. Here, we took advantage of the unique model provided by the malaria mosquito Anopheles gambiae s.l. to investigate the early evolution of several duplications, heterogeneous and homogeneous, segregating in natural populations from West Africa. These duplications encompass ~200 kb and 11 genes, including the adaptive insecticide resistance ace-1 locus. Through the survey of several populations from three countries over 3-4 years, we showed that an internal deletion of all coamplified genes except ace-1 is currently spreading in West Africa and introgressing from An. gambiae s.s. to An. coluzzii. Both observations provide evidences of its selection, most likely due to reducing the gene-dosage disturbances caused by the excessive copies of the nonadaptive genes. Our study thus provides a unique example of the early adaptive trajectory of duplications and underlines the role of the environmental conditions (insecticide treatment practices and species ecology). It also emphasizes the striking diversity of adaptive responses in these mosquitoes and reveals a worrisome process of resistance/cost trade-off evolution that could impact the control of malaria vectors in Africa.

SUBMITTER: Assogba BS

PROVIDER: S-EPMC6099818 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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Adaptive deletion in resistance gene duplications in the malaria vector <i>Anopheles gambiae</i>.

Assogba Benoît S BS Alout Haoues H Koffi Alphonsine A Penetier Cédric C Djogbénou Luc S LS Makoundou Patrick P Weill Mylène M Labbé Pierrick P

Evolutionary applications 20180325 8

While gene copy-number variations play major roles in long-term evolution, their early dynamics remains largely unknown. However, examples of their role in short-term adaptation are accumulating: identical repetitions of a locus (homogeneous duplications) can provide a quantitative advantage, while the association of differing alleles (heterogeneous duplications) allows carrying two functions simultaneously. Such duplications often result from rearrangements of sometimes relatively large chromos ...[more]

PMID: 30151037

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Project description:BACKGROUND:Metabolic resistance of the major malaria vector Anopheles gambiae (s.l.) to insecticides is operationally significant, particularly in combination with target site resistance. However, detection of metabolic resistance is not trivial and relies on laborious bioassays, unspecific biochemical methods, or sophisticated and expensive molecular approaches using transcriptomics. METHODS:Rapid one-step multiplex TaqMan-probe based RT-qPCR assays were developed and optimised to measure the expression levels of genes associated with metabolic insecticide resistance in An. gambiae (s.l.). Primers and probes were designed to target the mRNA of cytochrome P450-dependent monooxygenases CYP6P3, CYP6M2, CYP9K1, CYP6P4 and CYP6Z1, and the glutathione-S-transferase GSTE2. The novel assays were validated versus gold standard methods with a range of phenotyped mosquito specimens. The assays were also tested directly on lysates of RNAlater®-preserved mosquitoes without an RNA extraction step. RESULTS:The novel assays are efficient (reaction efficiencies = 95-109%), sensitive (covering a > 10.0 Ct range with R2 values > 0.99), specific (TaqMan chemistry), reproducible (%CV = 4.46-12.07%), as well as readily expandable to capture additional loci as they evolve or to cover additional species. The assays were successfully validated in terms of expression levels against standard two-step singleplex qPCR assays (overall % difference = -17.6%, 95% CI = -38.7-3.43%) and microarrays, using laboratory strains and field-caught samples. The assays can also be applied directly on lysates of mosquito specimens, without RNA extraction or DNase treatment. CONCLUSIONS:The novel multiplex assays for monitoring the levels of major detoxification genes and metabolic resistance in An. gambiae (s.l.) are simple to perform, robust and rapid. They may complement current diagnostic assays to provide evidence-based and operationally relevant information for insecticide resistance management.

Project description:Anopheles gambiae, An. coluzzii and An. arabiensis are the three major vectors of malaria in Nigeria. These mosquitoes have developed resistance to different insecticides. Insecticides resistance intensity assay was recently introduced to provide insight into the potential operational significance of insecticide resistance. Here, we present data on pyrethroids resistance intensity and resistance mechanisms from six vector surveillance sites (Lagos, Ogun, Edo, Anambra, Kwara and Niger) in Nigeria. Adult Anopheles reared from larval collections were tested using WHO insecticides susceptibility protocol with 1x concentration of permethrin and deltamethrin followed with intensity assays with 5x and 10x concentrations of both insecticides. Synergistic and biochemical assays were carried out and underlying resistance mechanisms determined following standard protocols. Anopheles gambiae constituted >50% samples tested in five sites. Permethrin and deltamethrin resistance was observed at all the sites. The Kdt50 varied from 15 minutes (CI = 13.6-17.2) in deltamethrin to 42.1 minutes (CI = 39.4-44.1) in permethrin. For both insecticides, Kdt95 was >30 minutes with 25% to 87% post exposure mortality at the different sites. The West Africa knock down resistance (kdr-w) mechanism was found at each site. Resistant An. gambiae from Lagos, Ogun and Niger synergized prior to permethrin or deltamethrin exposure showed significant mortality (89-100%) compared to unsynergized mosquitoes (Lagos, p = 0.031; Ogun, p = 0.025; Niger, p = 0.018). Biochemical analyses revealed significant increased levels of P450 enzymes in resistant Anopheles gambiae from Lagos (p = 0.038); Ogun (p = 0.042) and Niger (p = 0.028) in addition to GST in Lagos (p = 0.028) and Ogun (p = 0.033). Overall, the results revealed high pyrethroid resistance associated with increased activities of metabolic enzymes (P450 + GST) in An. gambiae and An. coluzzii from Lagos and Ogun. The presence of kdr + P450 conferred moderate resistance whereas low resistance was the case where kdr was the sole resistance mechanism. Findings thus suggests that elevated levels of cytochrome P450 enzymes together with GST were responsible for high or severe pyrethroid resistance.

Dataset Information

Adaptive deletion in resistance gene duplications in the malaria vector Anopheles gambiae.

Publications

Adaptive deletion in resistance gene duplications in the malaria vector <i>Anopheles gambiae</i>.

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