Influence of genetic polymorphism on transcriptional enhancer activity in the malaria vector Anopheles coluzzii

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Abstract
Enhancers are cis-regulatory elements that control most of the developmental and spatial gene expression in eukaryotes. Genetic variation of enhancer sequences is known to influence phenotypes, but the effect of enhancer variation upon enhancer functional activity and downstream phenotypes has barely been examined in any species. In the African malaria vector, Anopheles coluzzii , we identified a pilot set of candidate enhancers in the proximity of genes relevant for immunity, insecticide resistance, and development. The candidate enhancers were functionally validated using luciferase reporter assays, and their activity was found to be essentially independent of their physical orientation, a typical property of enhancers. All of the enhancer intervals segregated genetically polymorphic alleles, which displayed significantly different levels of functional activity, and inactive null alleles were also observed. Deletion mutagenesis and functional testing revealed a modular structure of positive and negative regulatory elements within the tested enhancers. The enhancer alleles carry genetic polymorphisms that also segregate in wild A. coluzzii populations in West Africa, indicating that enhancer variants with likely phenotypic consequences are frequent in nature. These results demonstrate the feasibility of screening for naturally polymorphic A. coluzzii enhancers that underlie important aspects of malaria transmission and vector biology.
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