Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes that transmit the disease1. To gain a deeper understanding of how mosquito populations are evolving, we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, identifying over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide resistance genes, with multiple sweeps spreading over large geographical distances and between species. The design of novel tools for mosquito control using gene drive will need to take account of high levels of genetic diversity in natural mosquito populations.

Highlights d African populations of Ae. aegypti vary in preference for human versus animal odor d Preference for humans is associated with intense dry seasons and urbanization d Preference for humans has a single, shared genomic basis inside and outside Africa d Rapid urbanization could further increase human biting in many African cities by 2050

The Afrotropical mosquito Anopheles gambiae sensu stricto (A. gambiae), a major vector of malaria, is currently undergoing speciation into the M and S molecular forms. These forms have diverged in larval ecology and reproductive behavior through unknown genetic mechanisms, despite considerable levels of hybridization. Previous genome-wide scans using gene-based microarrays uncovered divergence between M and S that was largely confined to gene-poor pericentromeric regions, prompting a speciation-with-ongoing-gene-flow model that implicated only ~3% of the genome near centromeres in the speciation process. Here, based on the complete M and S genome sequences, we report widespread and heterogeneous genomic divergence inconsistent with appreciable levels of inter-form gene flow, suggesting a more advanced speciation process and greater challenges to identify genes critical to initiating that process.

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Previous efforts to uncover the genetic underpinnings of ongoing ecological speciation of the M and S forms of the African malaria vector Anopheles gambiae revealed two centromere-proximal islands of genetic divergence on X and chromosome 2. Under the assumption of considerable ongoing gene flow between M and S, these persistently divergent genomic islands were widely considered to be “speciation islands”. In the course of microarray-based divergence mapping, we discovered a third centromere-associated island of divergence on chromosome 3, which was validated by targeted re-sequencing. To test for genetic association between the divergence islands on all three chromosomes, SNP-based assays were applied in four natural populations of M and S spanning West, Central and East Africa. Genotyping of 517 female M and S mosquitoes revealed nearly complete linkage disequilibrium between the centromeres of the three independently assorting chromosomes. These results suggest that despite the potential for inter-form gene flow through hybridization, actual (realized) gene flow between M and S may be substantially less than commonly assumed, and may not explain most shared variation. Moreover, the possibility of very low gene flow calls into question whether diverged pericentromeric regions-- characterized by reduced levels of variation and recombination-- are in fact instrumental rather than merely incidental to the speciation process.

The association between fitness-related phenotypic traits and an environmental gradient offers one of the best opportunities to study the interplay between natural selection and migration. In cases in which specific genetic variants also show such clinal patterns, it may be possible to uncover the mutations responsible for local adaptation. The malaria vector, Anopheles gambiae, is associated with a latitudinal cline in aridity in Cameroon; a large inversion on chromosome 2L of this mosquito shows large differences in frequency along this cline, with high frequencies of the inverted karyotype present in northern, more arid populations and an almost complete absence of the inverted arrangement in southern populations. Here we use a genome resequencing approach to investigate patterns of population divergence along the cline. By sequencing pools of individuals from both ends of the cline as well as in the center of the cline-where the inversion is present in intermediate frequency-we demonstrate almost complete panmixia across collinear parts of the genome and high levels of differentiation in inverted parts of the genome. Sequencing of separate pools of each inversion arrangement in the center of the cline reveals large amounts of gene flux (i.e., gene conversion and double crossovers) even within inverted regions, especially away from the inversion breakpoints. The interplay between natural selection, migration, and gene flux allows us to identify several candidate genes responsible for the match between inversion frequency and environmental variables. These results, coupled with similar conclusions from studies of clinal variation in Drosophila, point to a number of important biological functions associated with local environmental adaptation.

Access to reliable, rapid monitoring data is critical to guide response to an infectious disease outbreak. For pathogens that are shed in feces or urine, monitoring wastewater can provide a cost-effective snapshot of transmission in an entire community via a single sample.