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Exceptional diversity, maintenance of polymorphism, and recent directional selection on the APL1 malaria resistance genes of Anopheles gambiae.

Rottschaefer SM, Riehle MM, Coulibaly B, Sacko M, Niaré O, Morlais I, Traoré SF, Vernick KD, Lazzaro BP - PLoS Biol. (2011)

Bottom Line: Variation at APL1 is highly structured across geographic and temporal subpopulations.APL1 diversity is weakly stratified by the polymorphic 2La chromosomal inversion but is very strongly subdivided between the M and S "molecular forms." We find evidence that a recent selective sweep has occurred at the APL1 locus in M form mosquitoes only.The independently reported observation of a similar M-form restricted sweep at the Tep1 locus, whose product physically interacts with APL1C, suggests that epistatic selection may act on these two loci causing them to sweep coordinately.

View Article: PubMed Central - PubMed

Affiliation: Department of Entomology, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
The three-gene APL1 locus encodes essential components of the mosquito immune defense against malaria parasites. APL1 was originally identified because it lies within a mapped QTL conferring the vector mosquito Anopheles gambiae natural resistance to the human malaria parasite, Plasmodium falciparum, and APL1 genes have subsequently been shown to be involved in defense against several species of Plasmodium. Here, we examine molecular population genetic variation at the APL1 gene cluster in spatially and temporally diverse West African collections of A. gambiae. The locus is extremely polymorphic, showing evidence of adaptive evolutionary maintenance of genetic variation. We hypothesize that this variability aids in defense against genetically diverse pathogens, including Plasmodium. Variation at APL1 is highly structured across geographic and temporal subpopulations. In particular, diversity is exceptionally high during the rainy season, when malaria transmission rates are at their peak. Much less allelic diversity is observed during the dry season when mosquito population sizes and malaria transmission rates are low. APL1 diversity is weakly stratified by the polymorphic 2La chromosomal inversion but is very strongly subdivided between the M and S "molecular forms." We find evidence that a recent selective sweep has occurred at the APL1 locus in M form mosquitoes only. The independently reported observation of a similar M-form restricted sweep at the Tep1 locus, whose product physically interacts with APL1C, suggests that epistatic selection may act on these two loci causing them to sweep coordinately.

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Schematic representation of proteins encoded by APL1A, APL1B, and APL1C genes.The two major structural variants of APL1A are shown separately. APL1A1 alleles are characterized by the deletion of the PANGGL region. APL1A2 alleles carry an early stop codon that eliminates the coiled-coil domain.
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pbio-1000600-g001: Schematic representation of proteins encoded by APL1A, APL1B, and APL1C genes.The two major structural variants of APL1A are shown separately. APL1A1 alleles are characterized by the deletion of the PANGGL region. APL1A2 alleles carry an early stop codon that eliminates the coiled-coil domain.

Mentions: APL1A, APL1B, and APL1C are each composed of a small 5′ exon and longer second exon separated by a short intron [7]. Schematics of the encoded proteins are given in [7] and Figure 1. Each protein is characterized by an N-terminal signal peptide, a series of leucine-rich repeat (LRR) motifs spanning approximately 300 amino acids in the middle of the protein, and a coiled-coil domain at the C-terminus. APL1A2 alleles encode a premature stop codon that terminates the protein downstream of the LRR domain, eliminating the C-terminal coiled-coil from the predicted mature protein. We observed 5 APL1A1 alleles (out of 38 total sampled) in which the presumptive start codon has been mutated to ATA; it is unclear whether these alleles utilize an alternative ATG to initiate translation. APL1C alleles encode an N-terminal repeated motif of the amino acids P-A-N-G-G-L and related sequences (hereafter referred to as the PANGGL region). The APL1B gene does not have a PANGGL region. Interestingly, the PANGGL region is present in APL1A2 alleles but absent from APL1A1 [7]. In the course of the present study, we found that APL1A alleles of three species sister to A. gambiae (A. arabiensis, A. quadriannulatus, and A. merus) are all PANGGL-less and extremely similar to APL1A1 alleles, suggesting that APL1A2 alleles might be of recent evolutionary origin in A. gambiae. The deletion that eliminates PANGGL from APL1B relative to APL1C is 207 bp longer than and shares neither breakpoint with the insertion/deletion that distinguishes APL1A1 from APL1A2. Thus, there must have been at least two independent mutations resulting in either the gain or loss of the PANGGL region in APL1 genes. The similarity in sequence between the PANGGL repeats and flanking regions of APL1C and APL1A2 alleles, along with the apparent absence of APL1A2 alleles in A. merus, A. arabiensis, and A. quadriannulatus (Figure S1), suggests that PANGGL repeats may have been introduced into the APL1A gene via paralogous conversion with APL1C in A. gambiae. Elevated mutation rate due to the repetitive structure and potentially ongoing exchange between APL1C and APL1A2 might then generate allelic diversity in both genes. Paralogous gene conversion has similarly been hypothesized to explain the origin of divergent alleles of the Tep1 gene in A. gambiae [18]. No function has been determined for the PANGGL repeat region, but convergence of a PANGGL-less structure in APL1B and APL1A1 alleles and presence of PANGGL in APL1C and APL1A2 alleles suggests that presence/absence of the PANGGL domain may alter APL1 function and adaptive value. Testing this hypothesis will require manipulative experimentation.


Exceptional diversity, maintenance of polymorphism, and recent directional selection on the APL1 malaria resistance genes of Anopheles gambiae.

Rottschaefer SM, Riehle MM, Coulibaly B, Sacko M, Niaré O, Morlais I, Traoré SF, Vernick KD, Lazzaro BP - PLoS Biol. (2011)

Schematic representation of proteins encoded by APL1A, APL1B, and APL1C genes.The two major structural variants of APL1A are shown separately. APL1A1 alleles are characterized by the deletion of the PANGGL region. APL1A2 alleles carry an early stop codon that eliminates the coiled-coil domain.
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Related In: Results  -  Collection

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pbio-1000600-g001: Schematic representation of proteins encoded by APL1A, APL1B, and APL1C genes.The two major structural variants of APL1A are shown separately. APL1A1 alleles are characterized by the deletion of the PANGGL region. APL1A2 alleles carry an early stop codon that eliminates the coiled-coil domain.
Mentions: APL1A, APL1B, and APL1C are each composed of a small 5′ exon and longer second exon separated by a short intron [7]. Schematics of the encoded proteins are given in [7] and Figure 1. Each protein is characterized by an N-terminal signal peptide, a series of leucine-rich repeat (LRR) motifs spanning approximately 300 amino acids in the middle of the protein, and a coiled-coil domain at the C-terminus. APL1A2 alleles encode a premature stop codon that terminates the protein downstream of the LRR domain, eliminating the C-terminal coiled-coil from the predicted mature protein. We observed 5 APL1A1 alleles (out of 38 total sampled) in which the presumptive start codon has been mutated to ATA; it is unclear whether these alleles utilize an alternative ATG to initiate translation. APL1C alleles encode an N-terminal repeated motif of the amino acids P-A-N-G-G-L and related sequences (hereafter referred to as the PANGGL region). The APL1B gene does not have a PANGGL region. Interestingly, the PANGGL region is present in APL1A2 alleles but absent from APL1A1 [7]. In the course of the present study, we found that APL1A alleles of three species sister to A. gambiae (A. arabiensis, A. quadriannulatus, and A. merus) are all PANGGL-less and extremely similar to APL1A1 alleles, suggesting that APL1A2 alleles might be of recent evolutionary origin in A. gambiae. The deletion that eliminates PANGGL from APL1B relative to APL1C is 207 bp longer than and shares neither breakpoint with the insertion/deletion that distinguishes APL1A1 from APL1A2. Thus, there must have been at least two independent mutations resulting in either the gain or loss of the PANGGL region in APL1 genes. The similarity in sequence between the PANGGL repeats and flanking regions of APL1C and APL1A2 alleles, along with the apparent absence of APL1A2 alleles in A. merus, A. arabiensis, and A. quadriannulatus (Figure S1), suggests that PANGGL repeats may have been introduced into the APL1A gene via paralogous conversion with APL1C in A. gambiae. Elevated mutation rate due to the repetitive structure and potentially ongoing exchange between APL1C and APL1A2 might then generate allelic diversity in both genes. Paralogous gene conversion has similarly been hypothesized to explain the origin of divergent alleles of the Tep1 gene in A. gambiae [18]. No function has been determined for the PANGGL repeat region, but convergence of a PANGGL-less structure in APL1B and APL1A1 alleles and presence of PANGGL in APL1C and APL1A2 alleles suggests that presence/absence of the PANGGL domain may alter APL1 function and adaptive value. Testing this hypothesis will require manipulative experimentation.

Bottom Line: Variation at APL1 is highly structured across geographic and temporal subpopulations.APL1 diversity is weakly stratified by the polymorphic 2La chromosomal inversion but is very strongly subdivided between the M and S "molecular forms." We find evidence that a recent selective sweep has occurred at the APL1 locus in M form mosquitoes only.The independently reported observation of a similar M-form restricted sweep at the Tep1 locus, whose product physically interacts with APL1C, suggests that epistatic selection may act on these two loci causing them to sweep coordinately.

View Article: PubMed Central - PubMed

Affiliation: Department of Entomology, Cornell University, Ithaca, New York, United States of America.

ABSTRACT
The three-gene APL1 locus encodes essential components of the mosquito immune defense against malaria parasites. APL1 was originally identified because it lies within a mapped QTL conferring the vector mosquito Anopheles gambiae natural resistance to the human malaria parasite, Plasmodium falciparum, and APL1 genes have subsequently been shown to be involved in defense against several species of Plasmodium. Here, we examine molecular population genetic variation at the APL1 gene cluster in spatially and temporally diverse West African collections of A. gambiae. The locus is extremely polymorphic, showing evidence of adaptive evolutionary maintenance of genetic variation. We hypothesize that this variability aids in defense against genetically diverse pathogens, including Plasmodium. Variation at APL1 is highly structured across geographic and temporal subpopulations. In particular, diversity is exceptionally high during the rainy season, when malaria transmission rates are at their peak. Much less allelic diversity is observed during the dry season when mosquito population sizes and malaria transmission rates are low. APL1 diversity is weakly stratified by the polymorphic 2La chromosomal inversion but is very strongly subdivided between the M and S "molecular forms." We find evidence that a recent selective sweep has occurred at the APL1 locus in M form mosquitoes only. The independently reported observation of a similar M-form restricted sweep at the Tep1 locus, whose product physically interacts with APL1C, suggests that epistatic selection may act on these two loci causing them to sweep coordinately.

Show MeSH
Related in: MedlinePlus