{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:47:13Z","timestamp":1791586033948,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010678","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["101893\/Z\/13\/Z"],"award-info":[{"award-number":["101893\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["217188\/Z\/19\/Z"],"award-info":[{"award-number":["217188\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-006003"],"award-info":[{"award-number":["INV-006003"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Cross-resistance to insecticides in multiple resistant malaria vectors is hampering resistance management. Understanding its underlying molecular basis is critical to implementation of suitable insecticide-based interventions. Here, we established that the tandemly duplicated cytochrome P450s,\n                    <jats:italic>CYP6P9a\/b<\/jats:italic>\n                    are driving carbamate and pyrethroid cross-resistance in Southern African populations of the major malaria vector\n                    <jats:italic>Anopheles funestus<\/jats:italic>\n                    .\n                  <\/jats:p>\n                  <jats:p>\n                    Transcriptome sequencing revealed that cytochrome P450s are the most over-expressed genes in bendiocarb and permethrin-resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    . The\n                    <jats:italic>CYP6P9a<\/jats:italic>\n                    and\n                    <jats:italic>CYP6P9b<\/jats:italic>\n                    genes are overexpressed in resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    from Southern Africa (Malawi) versus susceptible\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    (Fold change (FC) is 53.4 and 17 respectively), while the\n                    <jats:italic>CYP6P4a<\/jats:italic>\n                    and\n                    <jats:italic>CYP6P4b<\/jats:italic>\n                    genes are overexpressed in resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    in Ghana, West Africa, (FC is 41.1 and 17.2 respectively). Other up-regulated genes in resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    include several additional cytochrome P450s (e.g.\n                    <jats:italic>CYP9J5<\/jats:italic>\n                    ,\n                    <jats:italic>CYP6P2<\/jats:italic>\n                    ,\n                    <jats:italic>CYP6P5<\/jats:italic>\n                    ), glutathione-S transferases, ATP-binding cassette transporters, digestive enzymes, microRNA and transcription factors (FC&lt;7). Targeted enrichment sequencing strongly linked a known major pyrethroid resistance locus (\n                    <jats:italic>rp1<\/jats:italic>\n                    ) to carbamate resistance centering around\n                    <jats:italic>CYP6P9a\/b<\/jats:italic>\n                    . In bendiocarb resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    , this locus exhibits a reduced nucleotide diversity, significant p-values when comparing allele frequencies, and the most non-synonymous substitutions. Recombinant enzyme metabolism assays showed that both\n                    <jats:italic>CYP6P9a\/b<\/jats:italic>\n                    metabolize carbamates. Transgenic expression of\n                    <jats:italic>CYP6P9a\/b<\/jats:italic>\n                    in\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    revealed that flies expressing both genes were significantly more resistant to carbamates than controls. Furthermore, a strong correlation was observed between carbamate resistance and\n                    <jats:italic>CYP6P9a<\/jats:italic>\n                    genotypes with homozygote resistant\n                    <jats:italic>An<\/jats:italic>\n                    .\n                    <jats:italic>funestus<\/jats:italic>\n                    (\n                    <jats:italic>CYP6P9a<\/jats:italic>\n                    and the 6.5kb enhancer structural variant) exhibiting a greater ability to withstand bendiocarb\/propoxur exposure than homozygote CYP6P9a_susceptible (e.g Odds ratio = 20.8, P&lt;0.0001 for bendiocarb) and heterozygotes (OR = 9.7, P&lt;0.0001). Double homozygote resistant genotype (RR\/RR) were even more able to survive than any other genotype combination showing an additive effect.\n                  <\/jats:p>\n                  <jats:p>This study highlights the risk that pyrethroid resistance escalation poses to the efficacy of other classes of insecticides. Available metabolic resistance DNA-based diagnostic assays should be used by control programs to monitor cross-resistance between insecticides before implementing new interventions.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010678","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:38:27Z","timestamp":1679924307000},"page":"e1010678","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":48,"title":["The duplicated P450s CYP6P9a\/b drive carbamates and pyrethroids cross-resistance in the major African malaria vector Anopheles funestus"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-9608","authenticated-orcid":true,"given":"Leon M. J.","family":"Mugenzi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theofelix","family":"A. Tekoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0744-802X","authenticated-orcid":true,"given":"Sulaiman","family":"S. Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6438-4897","authenticated-orcid":true,"given":"Abdullahi","family":"Muhammad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mersimine","family":"Kouamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murielle J.","family":"Wondji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Irving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3358-4949","authenticated-orcid":true,"given":"Jack","family":"Hearn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0791-3673","authenticated-orcid":true,"given":"Charles S.","family":"Wondji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"pgen.1010678.ref001","author":"WHO","year":"2022"},{"issue":"7572","key":"pgen.1010678.ref002","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nature15535","article-title":"The effect of malaria control on Plasmodium falciparum in Africa 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