Natural Malaria Infection in Anopheles gambiae Is Regulated by a Single Genomic Control Region

Abstract

We surveyed an Anopheles gambiae population in a West African malaria transmission zone for naturally occurring genetic loci that control mosquito infection with the human malaria parasite, Plasmodium falciparum. The strongest Plasmodium resistance loci cluster in a small region of chromosome 2L and each locus explains at least 89% of parasite-free mosquitoes in independent pedigrees. Together, the clustered loci form a genomic Plasmodium-resistance island that explains most of the genetic variation for malaria parasite infection of mosquitoes in nature. Among the candidate genes in this chromosome region, RNA interference knockdown assays confirm a role in Plasmodium resistance for Anopheles Plasmodium-responsive leucine-rich repeat 1 (APL1), encoding a leucine-rich repeat protein that is similar to molecules involved in natural pathogen resistance mechanisms in plants and mammals.

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

“…The major malaria resistance locus, PRI, has 56 conserved syntenic blocks with a median length of ∼45 kb. The PRI was detected previously in mosquitoes with a chromosomal inversion between 20,528,089 and 42,165,532 bp (4,9,19). However, our map is based on the pink-eye standard (PEST) strain, which lacks this inversion, being used as the reference genome.…”

“…This strategy differs from approaches that determine candidate genes on the basis of the differentially expressed genes under parasite challenge. Seventy known genes were used to label genomic blocks on the expression The PRI was detected originally in mosquitoes with a chromosomal inversion that is absent in the reference genome strain (4,9,19). This results in two noncontiguous PRI domains in the map shown here.…”

“…2B) . Interestingly, the products of several of the 13 immune genes, including APL1C, CTLs, serpins, and caspases, are reported to be involved in the defense against parasite infection (4,(22)(23)(24). Therefore, we further analyzed the profile β conserved genomic blocks within the PRI for possible roles in immunity against Plasmodium parasites.…”

“…gambiae populations; previous genetic mapping studies identified several contributing loci. A major parasite resistance island (PRI) was identified on the basis of segregation in two parental strains, with differences in vector competence originating in Eastern and Western Africa (4,9). However, identification of the malaria resistance genes within the PRI in wildderived mosquitoes is a significant challenge because the locus is large (>10 Mb) and it is difficult to acquire sufficient samples for direct-association studies.…”

“…Many genes related to innate immunity have been reported (3)(4)(5). Among these are pattern recognition receptors, including leucine-rich-repeats proteins, fibrinogen-related protein family members (FREPs or FBNs), thioester-containing proteins (TEPs), and C-type lectins (CTLs).…”