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A 6.5kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy (lay summary)

his is a lay summary of the article published under the DOI: 10.1101/2020.05.05.078600

Published onJun 05, 2023
A 6.5kb intergenic structural variation enhances P450-mediated resistance to pyrethroids in malaria vectors lowering bed net efficacy (lay summary)


Elucidating the complex evolutionary armory that mosquitoes deploy against insecticides is crucial to maintain the effectiveness of insecticide-based interventions.

Here, we deciphered the role of a 6.5kb structural variation (SV) in driving cytochrome P450-mediated pyrethroid resistance in the malaria vector, Anopheles funestus.

Whole genome pooled sequencing detected an intergenic 6.5kb SV between duplicated CYP6P9a/b P450s in pyrethroid resistant mosquitoes through a translocation event.

Promoter analysis revealed a 17.5-fold higher activity (P<0.0001) for the SV-carrying fragment than the SV-free one.

qRT-PCR expression profiling of CYP6P9a/b for each SV genotype supported its role as an enhancer since SV+/SV+ homozygote mosquitoes had significantly greater expression for both genes than heterozygotes SV+/SV- (1.7-2-fold) and homozygotes SV-/SV- (4-5-fold).

Designing a PCR assay revealed a strong association between this SV and pyrethroid resistance (SV+/SV+ vs SV-/SV-; OR=2079.4, P=<0.001).

The 6.5kb SV is present at high frequency in southern Africa (80-100%) but absent in East/Central/West Africa.

Experimental hut trials revealed that homozygote SV mosquitoes had significantly greater chance to survive exposure to pyrethroid-treated Nets (OR 27.7; P < 0.0001) and to blood feed than susceptible.

Furthermore, triple homozygote resistant (SV+/CYP6P9a_R/CYP6P9b_R) exhibit a higher resistance level leading to a far superior ability to survive exposure to nets than triple susceptible mosquitoes, revealing a strong additive effect.

This study highlights the important role of structural variations in the development of insecticide resistance in malaria vectors and their detrimental impact on the effectiveness of pyrethroid-based nets.

Scientists identify DNA mutations that allow southern African mosquitos to survive insecticides

Scientists have identified a stretch of DNA that helps mosquitoes resist a chemical meant to kill them (insecticides).

This DNA stretch seems to boost genes that allow southern African mosquitos to better process pyrethroid, a common insecticide used in nets to prevent mosquitoes from spreading malaria to people.

Insecticide-treated nets is one of the main ways to prevent mosquitoes who carry malaria from spreading the disease to humans.

However, recently mosquitoes appear to be surviving despite being exposed to deadly insecticides.

Scientists want to pinpoint the biological reason behind this insecticide resistance so that anti-mosquito nets can be improved to control malaria.

In this study, researchers wanted to show how a stretch of mutated DNA in malarial mosquitoes increases resistance to the insecticide pyrethroid.

They also wanted to see if this genetic adaptation is found in mosquitos in different regions of Africa.

The researchers analysed the DNA of various mosquito populations, and checked how resistant the mosquitos were to pyrethroid.

They used computer modelling, laboratory experiments, and trials with mosquitoes released in experimental huts to draw their conclusions.

They found that the presence of the DNA led to malarial mosquitoes developing resistance to the insecticide-treated nets.

All the mosquitoes that were resistant to pyrethroid in this study had the large, mutated DNA stretch.

But interestingly, these mosquitos were from southern Africa; the mutation was not found in malarial mosquitoes in west, east or central Africa.

While scientists already knew that mosquitos carrying malaria are becoming resistant to the chemicals we use to kill them, this study explains how they are able to evade insecticides on a genetic level.

The researchers also developed a new method to monitor the DNA mutation in mosquitoes, which will be useful for other scientists looking into this in future.

The researchers suggest that future work should look more deeply into these kinds of mutated DNA sequences and how exactly they affect resistance genes in malarial mosquitoes.

This study by Cameroonian researchers shows that we need new ways to control the spread of Malaria, especially in southern Africa, where we now have DNA evidence as to why mosquitos are able to evade insecticide-treated nets.

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