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Mosquito Genomes Reveal High Diversity, Movement of Insecticide Resistance Genes

NEW YORK (GenomeWeb) – The mosquitos that transmit malaria are among the most genetically diverse eukaryotes, according to a new sequencing study, which could have ramifications for population and disease transmission control efforts, including gene drives.

Researchers from the Anopheles gambiae 1000 Genomes Project sequenced 765 A. gambiae sensu stricto and A. coluzzii individuals captured in 15 different spots in eight African countries. Together, those two mosquito species account for the majority of Plasmodium falciparum malaria in Africa. As they reported in Nature today, the researchers uncovered complex population structure, evidence of gene flow, and signals of recent selection on insecticide-resistance genes within the mosquitos' genomes.

"The diversity of mosquito genomes was far greater than we expected," study author Mara Lawniczak, from the Wellcome Trust Sanger Institute, said in a statement. "Such high levels of genetic variation poise mosquito populations to rapidly evolve in response to our efforts to control them, whether that be with insecticides or any other control measure, including gene drive."

The researchers sequenced the wild mosquitos they caught on the Illumina HiSeq platform and aligned the reads they generated against the AgamP3 reference genome. All in all, they uncovered more than 52 million high-quality SNPs and noted an average nucleotide diversity of 1.5 percent and more than 3 percent at synonymous coding sites among the mosquito populations. This, the researchers said, confirmed that these mosquitos are among the most diverse eukaryotic species.

However, Lawniczak and her colleagues noted that this high level of natural diversity could stymie efforts to control mosquito populations using CRISPR-Cas9-based gene drives. Researchers exploring gene drives typically use them to render a pest species infertile. Polymorphisms within the Cas9 target site, though, could prevent its recognition and limit gene drives' efficacy. Instead, the researchers said gene drives would likely have to target multiple sites within the same gene.

At the same time, the researchers uncovered patterns of relatedness among the mosquito populations. Some, for instance, shared large chromosomal inversions, while others had similar pericentromeric regions. They further traced the mosquitos back to five major ancestral populations.

The mosquitos' genomes also provided evidence that mosquitos may migrate seasonally, beyond their typical three-mile range. Migration, the researchers noted, could enable the spread of insecticide resistance genes.

Lawniczak and her colleagues reported evidence of gene flow between the two mosquito species. For instance, one gene region — which harbors the insecticide-related Vgsc gene — introgressed from An. gambiae into An. coluzzii in Burkina Faso and Angola. Additionally, the researchers found that mosquitos in Guinea-Bissau harbor a mixture of alleles from both species on all their chromosomes, as do coastal Kenyan mosquitos, a finding that surprised the researchers as An. coluzzii were not thought to extend beyond the East African Rift.

The mosquito genomes also contained strong signals of positive selection at insecticide resistance-linked genes, including the Vgsc, Gste, Gste2, and Cyp6p genes. Resistance at the Vgsc gene, which reduces susceptibility to DDT, is tied to two kdr alleles, Leu995Phe and Leu995Ser. Leu995Phe is common among mosquitos in West and Central Africa, while Leu995Ser variant is more common among Central and East African mosquitos. The researchers also uncovered other alleles under selection that could enhance resistance.

"The data we have generated are a unique resource for studying how mosquito populations are responding to our current control efforts, and for designing better technologies and strategies for mosquito control in the future," lead author Alistair Miles, from the University of Oxford and the Wellcome Trust Sanger Institute, added in the statement.