Journal Article Ppublish
PubMed: 41133746 DOI: 10.1093/molbev/msaf251
Genomic Drivers of Pyrethroid Resistance Escalation in the Malaria Vector Anopheles funestus Across Africa.
Mol Biol Evol 42(10)
Authors: Mahamat Gadji, Hervé Raoul Tazokong, Mersimine F M Kouamo, Magellan Tchouakui, Murielle Wondji, Leon M J Mugenzi, Helen Irving, Jack Hearn, Sulaiman S Ibrahim, Charles S Wondji
Affiliations
- Department of Vector Genomics, Centre for Research in Infectious Diseases (CRID), P.O. BOX 13591, Yaoundé, Cameroon.
- Department of Microbiology, University of Yaoundé 1, P.O. BOX 812, Yaoundé, Cameroon.
- Vector Biology Department, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK.
- Syngenta Crop Protection, Werk Stein, Stein, Switzerland.
- Centre for Epidemiology and Planetary Health, Scotland's Rural College (SRUC), RAVIC, Inverness, UK.
- Department of Biochemistry, Bayero University, PMB 3011, Kano, Nigeria.
Abstract
Aggravation of pyrethroid resistance threatens malaria control; yet, its molecular basis remains elusive. This study used a comprehensive multi-omics framework integrating 7-year gap temporal RNA-Seq, PoolSeq Whole Genome, and functional analyses, to uncover resistance escalation mechanisms in Anopheles funestus Africa-wide. Spatiotemporal analyses (2014-2021) reveal massive overexpression of novel genes (V-ATPase, tubulin alpha-1, transposase), alongside canonical resistance genes (P450s, cuticular proteins, chemosensory). Epigenetic regulators (histone H3/4, glycine N-methyltransferase) were greatly overexpressed in highly resistant mosquitoes, suggesting resistance modulation. P450-based signatures of selective sweep were detected with a drastic change in the rp1 and the P450 CYP9K1 in Central Africa. Noticeably, genomic variations at the cytochrome P450 reductase (CPR) gene were selected including a N70I mutation in Malawi [0% (2009)-80% (2021)] and a 5.9 kb promoter duplication in Ghana. Transgenic expression in Drosophila confirmed CPR-70I enhances pyrethroid resistance when co-expressed with P450-CYP6P9a, uncovering a novel CPR-mediated mechanism in intensely resistant mosquitoes. This study highlights novel candidate genes for marker development to track the spread of intensely resistant mosquitoes across Africa.
MeSH
Genes, Malaria, Molecular Biology