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

Li, Jun, Wang, Xiaohong, Zhang, Genwei, Githure, John I., Yan, Guiyun, James, Anthony A.
Proceedings of the National Academy of Sciences of the United States of America 2013 v.110 no.51 pp. 20675-20680
Anopheles gambiae, Plasmodium falciparum, RNA interference, adenosine deaminase, genes, genetic variation, high-throughput nucleotide sequencing, insect vectors, malaria, parasites, phenotype, single nucleotide polymorphism, Kenya
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.