Abstract
Nucleotide variation patterns across species are shaped by the processes of natural selection, including exposure to environmental pathogens. We examined patterns of genetic variation in two sister species, Anopheles gambiae and Anopheles coluzzii, both efficient natural vectors of human malaria in West Africa. We used the differentiation signature displayed by a known coordinate selective sweep of immune genes APL1 and TEP1 in A. coluzzii to design a population genetic screen trained on the sweep, classified a panel of 26 potential immune genes for concordance with the signature, and functionally tested their immune phenotypes. The screen results were strongly predictive for genes with protective immune phenotypes: genes meeting the screen criteria were significantly more likely to display a functional phenotype against malaria infection than genes not meeting the criteria (p = 0.0005). Thus, an evolution-based screen can efficiently prioritize candidate genes for labor-intensive downstream functional testing, and safely allow the elimination of genes not meeting the screen criteria. The suite of immune genes with characteristics similar to the APL1-TEP1 selective sweep appears to be more widespread in the A. coluzzii genome than previously recognized. The immune gene differentiation may be a consequence of adaptation of A. coluzzii to new pathogens encountered in its niche expansion during the separation from A. gambiae, although the role, if any of natural selection by Plasmodium is unknown. Application of the screen allowed identification of new functional immune factors, and assignment of new functions to known factors. We describe biochemical binding interactions between immune proteins that underlie functional activity for malaria infection, which highlights the interplay between pathogen specificity and the structure of immune complexes. We also find that most malaria-protective immune factors display phenotypes for either human or rodent malaria, with broad specificity a rarity.
Highlights
Malaria remains a serious global public health concern
An index of population differentiation generates three candidate gene clusters We analyzed population-based sequence datasets for two criteria of genetic differentiation modeled on the APL1 and TEP1 genes: i) low ratio of A. coluzzii to A. gambiae nucleotide diversity, and ii) high pairwise Fst between A. coluzzii and A. gambiae
Detection of differentiation between species for genes in Clusters 1 and 2 is not a consequence of low overall diversity in A. coluzzii, because diversity levels are not different across clusters in A. coluzzii or A. gambiae (WMW, p = 0.850). These results suggested that parameters of population genetic differentiation of A. coluzzii from the ancestral form, A. gambiae, could be informative for immune function, at least against malaria parasites
Summary
Malaria remains a serious global public health concern. In Africa, members of the Anopheles gambiae species complex are primary mosquito vectors of the human malaria parasite, Plasmodium falciparum. The A. gambiae complex consists of at least eight morphologically identical sibling species. Previous studies have characterized population structure of the A. gambiae complex, focusing on the sympatric subgroups originally named the M and S molecular forms of A. gambiae sensu stricto, which were renamed as A. coluzzii and A. gambiae, respectively [1]. Most genome-wide genetic variation is shared between A. coluzzii and A. gambiae. Genomic regions of differentiation were described, termed speciation islands [9,10,11], the role of these islands in population differentiation or speciation currently remains unresolved [12, 13]
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