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Genome-block expression-assisted association studies discover malaria resistance genes in Anopheles gambiae.

ABSTRACT: The malaria parasite-resistance island (PRI) of the African mosquito vector, Anopheles gambiae, was mapped to five genomic regions containing 80 genes, using coexpression patterns of genomic blocks. High-throughput sequencing identified 347 nonsynonymous single-nucleotide polymorphisms within these genes in mosquitoes from malaria-endemic areas in Kenya. Direct association studies between nonsynonymous single-nucleotide polymorphisms and Plasmodium falciparum infection identified three naturally occurring genetic variations in each of three genes (An. gambiae adenosine deaminase, fibrinogen-related protein 30, and fibrinogen-related protein 1) that were associated significantly with parasite infection. A role for these genes in the resistance phenotype was confirmed by RNA interference knockdown assays. Silencing fibrinogen-related protein 30 increased parasite infection significantly, whereas ablation of fibrinogen-related protein 1 transcripts resulted in mosquitoes nearly free of parasites. The discovered genes and single-nucleotide polymorphisms are anticipated to be useful in the development of tools for malaria control in endemic areas in Africa.

SUBMITTER: Li J

PROVIDER: S-EPMC3870758 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Genome-block expression-assisted association studies discover malaria resistance genes in Anopheles gambiae.

Li Jun J Wang Xiaohong X Zhang Genwei G Githure John I JI Yan Guiyun G James Anthony A AA

Proceedings of the National Academy of Sciences of the United States of America 20131202 51

The malaria parasite-resistance island (PRI) of the African mosquito vector, Anopheles gambiae, was mapped to five genomic regions containing 80 genes, using coexpression patterns of genomic blocks. High-throughput sequencing identified 347 nonsynonymous single-nucleotide polymorphisms within these genes in mosquitoes from malaria-endemic areas in Kenya. Direct association studies between nonsynonymous single-nucleotide polymorphisms and Plasmodium falciparum infection identified three naturally ...[more]

PMID: 24297936

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Project description:As pathogens that circumvent the host immune response are favoured by selection, so are host alleles that reduce parasite load. Such evolutionary processes leave their signature on the genes involved. Deciphering modes of selection operating on immune genes might reveal the nature of host-pathogen interactions and factors that govern susceptibility in host populations. Such understanding would have important public health implications.We analyzed polymorphisms in four mosquito immune genes (SP14D1, GNBP, defensin, and gambicin) to decipher selection effects, presumably mediated by pathogens. Using samples of Anopheles arabiensis, An. quadriannulatus and four An. gambiae populations, as well as published sequences from other Culicidae, we contrasted patterns of polymorphisms between different functional units of the same gene within and between populations. Our results revealed selection signatures operating on different time scales. At the most recent time scale, within-population diversity revealed purifying selection. Between populations and between species variation revealed reduced differentiation (GNBP and gambicin) at coding vs. noncoding- regions, consistent with balancing selection. McDonald-Kreitman tests between An. quadriannulatus and both sibling species revealed higher fixation rate of synonymous than nonsynonymous substitutions (GNBP) in accordance with frequency dependent balancing selection. At the longest time scale (>100 my), PAML analysis using distant Culicid taxa revealed positive selection at one codon in gambicin. Patterns of genetic variation were independent of exposure to human pathogens.Purifying selection is the most common form of selection operating on immune genes as it was detected on a contemporary time scale on all genes. Selection for "hypervariability" was not detected, but negative balancing selection, detected at a recent evolutionary time scale between sibling species may be rather common. Detection of positive selection at the deepest evolutionary time scale suggests that it occurs infrequently, possibly in association with speciation events. Our results provided no evidence to support the hypothesis that selection was mediated by pathogens that are transmitted to humans.

Project description:Anopheles gambiae, An. coluzzii and An. arabiensis are the three major vectors of malaria in Nigeria. These mosquitoes have developed resistance to different insecticides. Insecticides resistance intensity assay was recently introduced to provide insight into the potential operational significance of insecticide resistance. Here, we present data on pyrethroids resistance intensity and resistance mechanisms from six vector surveillance sites (Lagos, Ogun, Edo, Anambra, Kwara and Niger) in Nigeria. Adult Anopheles reared from larval collections were tested using WHO insecticides susceptibility protocol with 1x concentration of permethrin and deltamethrin followed with intensity assays with 5x and 10x concentrations of both insecticides. Synergistic and biochemical assays were carried out and underlying resistance mechanisms determined following standard protocols. Anopheles gambiae constituted >50% samples tested in five sites. Permethrin and deltamethrin resistance was observed at all the sites. The Kdt50 varied from 15 minutes (CI = 13.6-17.2) in deltamethrin to 42.1 minutes (CI = 39.4-44.1) in permethrin. For both insecticides, Kdt95 was >30 minutes with 25% to 87% post exposure mortality at the different sites. The West Africa knock down resistance (kdr-w) mechanism was found at each site. Resistant An. gambiae from Lagos, Ogun and Niger synergized prior to permethrin or deltamethrin exposure showed significant mortality (89-100%) compared to unsynergized mosquitoes (Lagos, p = 0.031; Ogun, p = 0.025; Niger, p = 0.018). Biochemical analyses revealed significant increased levels of P450 enzymes in resistant Anopheles gambiae from Lagos (p = 0.038); Ogun (p = 0.042) and Niger (p = 0.028) in addition to GST in Lagos (p = 0.028) and Ogun (p = 0.033). Overall, the results revealed high pyrethroid resistance associated with increased activities of metabolic enzymes (P450 + GST) in An. gambiae and An. coluzzii from Lagos and Ogun. The presence of kdr + P450 conferred moderate resistance whereas low resistance was the case where kdr was the sole resistance mechanism. Findings thus suggests that elevated levels of cytochrome P450 enzymes together with GST were responsible for high or severe pyrethroid resistance.

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Genome-block expression-assisted association studies discover malaria resistance genes in Anopheles gambiae.

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Genome-block expression-assisted association studies discover malaria resistance genes in Anopheles gambiae.

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