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Title: Investigating population structure and mechanisms driving pyrethroid resistance in Anopheles funestus reveals a selective sweep in Southern Africa
Author: Barnes, Kayla
ISNI:       0000 0004 5369 013X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2015
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Resistance to pyrethroids, the only insecticide class approved for bednets, threatens the control of the major African malaria vectors, Anopheles funestus. In Malawi, where resistance has been previously reported, little is known about the nation-wide resistance profile, mechanisms and patterns of gene flow driving the spread of resistance. To manage resistance effectively, it is crucial to understand the dynamics and evolution of resistance. To fill this gap in knowledge, this study has determined the levels of insecticide resistance in Malawi in a South/North transect across the highly endemic and densely populated lake and southern agricultural area. An. funestus was resistant to pyrethroids, carbamates, and DDT but fully susceptible to organophosphates. Microarray and qRT-PCR analysis revealed the key role of cytochrome P450 genes including as CYP6P9a, CYP6P9b and CYP6M7. However, a significant shift in the over-expression of these CYP450s was detected across a south/north transect, with CYP6M7 more highly over-transcribed in the two northern locations and CYP6P9a and CYP6P9b more greatly over-transcribed in the south. CYP6M7 was under neutral selection while CYP6P9a and CYP6P9b were directionally selected, which was more pronounced in the South than in the North. Additionally, a new CYP450 gene, CYP6AA1, located on the pyrethroid resistance QTL (rp1) near CYP6P9a and CYP6P9b, was consistently overexpressed in resistant mosquitoes (5.20 < Fold change < 12.66) yet maintains neutral selection. This variation in gene expression may suggest some restrictions to gene flow across Malawian populations, therefore, the population structure of Malawian An. funestus populations and those from southern Africa was determined using genome-widely distributed microsatellite markers. This analysis revealed a significant genetic differentiation between southern and northern Malawi based on Fst and clustering with STRUCTURE with detection of three population clusters that corresponded to the shift in gene expression between CYP6P9a and CYP6P9b and CYP6M7. A signature of selective sweep was detected as samples collected before intervention in southern Malawi and Mozambique exhibited as significant loss of diversity around the pyrethroid resistance QTL 1 (rp1) on the 2R chromosome, spanning the CYP6P9a and CYP6P9b genes. A detailed sequencing analysis of five regions spanning this 120kb rp1 revealed a significant loss of diversity occurred around CYP6P9a and CYP6P9b in samples collected post intervention but not in samples collected before intervention. This study highlights the importance of characterizing nation-wide variations in vector populations in order to design successful resistance management strategies and highlights the genetic complexity of resistance in major mosquito malaria vectors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General)