Restriction to gene flow is associated with changes in the molecular basis of pyrethroid resistance in the malaria vector Anopheles funestus

Abstract

Resistance to pyrethroids, the sole insecticide class recommended for treating bed nets, threatens the control of major malaria vectors, including Anopheles funestus. Effective management of resistance requires an understanding of the dynamics and mechanisms driving resistance. Here, using genome-wide transcription and genetic diversity analyses, we show that a shift in the molecular basis of pyrethroid resistance in southern African populations of this species is associated with a restricted gene flow. Across the most highly endemic and densely populated regions in Malawi, An. funestus is resistant to pyrethroids, carbamates, and organochlorides. Genome-wide microarray-based transcription analysis identified overexpression of cytochrome P450 genes as the main mechanism driving this resistance. The most up-regulated genes include cytochrome P450s (CYP) CYP6P9a, CYP6P9b and CYP6M7. However, a significant shift in the overexpression profile of these genes was detected across a south/north transect, with CYP6P9a and CYP6P9b more highly overexpressed in the southern resistance front and CYP6M7 predominant in the northern front. A genome-wide genetic structure analysis of southern African populations of An. funestus from Zambia, Malawi, and Mozambique revealed a restriction of gene flow between populations, in line with the geographical variation observed in the transcriptomic analysis. Genetic polymorphism analysis of the three key resistance genes, CYP6P9a, CYP6P9b, and CYP6M7, support barriers to gene flow that are shaping the underlying molecular basis of pyrethroid resistance across southern Africa. This barrier to gene flow is likely to impact the design and implementation of resistance management strategies in the region.

Genetic differentiation and population structure of Anopheles funestus from Uganda and the southern African countries of Malawi, Mozambique, Zambia and Zimbabwe

“…A study on upregulation of insecticide resistance metabolic enzyme genes provided evidence of population structuring between northern and southern sites in Malawi [16]. The Mantel test used here for correlation of genetic variation with geographical distance (isolation by distance hypothesis) showed positive correlation between sites in Malawi (R xy = 0.083, P = 0.007), not indicating environmental or other barriers to gene flow.…”

“…In east and southern Africa, studies focused on the population structure of An. funestus have been carried out in Uganda [12][13][14], Malawi [12,[15][16][17], Kenya [18], Tanzania [19], Mozambique [12,16,17] and Zambia [16]. These and other studies have revealed various levels of differentiation over the African continent, from no or very low structure to high population structure of An.…”

“…These and other studies have revealed various levels of differentiation over the African continent, from no or very low structure to high population structure of An. funestus [12][13][14][15][16][17][18][19].…”

Beyond frontiers: On invasive alien mosquito species in America and Europe

“…Anthropogenic land use and land cover transformation and the subsequent increase in human population densities in large cities are important drivers for the demographic expansion of A. aegypti in a microgeographic scale [22], but there is a lack in understanding of how mosquito vectors are adapting to urban environments to make it possible for them to prosper and increase their range and abundance. Furthermore, the role of preselected insecticide resistance alleles in the success of a given invasive species to adapt to their new environments is currently overlooked and may impact their spreading, establishment, and genetic variability [23].…”

The implementation of long-lasting insecticidal bed nets has differential effects on the genetic structure of the African malaria vectors in the Anopheles gambiae complex in Dielmo, Senegal

“…Over the last decade, impressive progress has been made in controlling malaria vectors in sub-Saharan Africa mainly using long-lasting insecticidal bed nets (LLINs) and indoor residual spraying (IRS) [ 1 ]. Both tools have remarkably contributed to the decrease of malaria prevalence since 2000 [ 2 ] in sub-Saharan Africa, where the burden of malaria is heaviest [ 3 ].…”