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The Genome Sequence of the Malaria Mosquito Anopheles gambiae
By R. A. Holt et al.; Science 298, 129 (2002)

Image Credit: Center for Disease Control;
James D. Gathany -- Public Health Image Library.

Foremost in our minds is how the genomic and EST data can be used to improve control of malaria in the coming decades. Three issues are central to efforts aimed at reducing malaria transmission: reducing the numbers and longevity of infectious mosquitoes, understanding what attracts them to human (as opposed to animal) hosts, and reducing the capacity of parasites to fully develop within them.



Reducing the number of mosquitoes:
Anopheline mosquitoes rapidly develop resistance to pesticides. The molecular targets of the major classes of insecticides are known, and mutation of target sites is well understood as a mechanism of resistance. However, the molecular basis of metabolic resistance is less clear. The Anopheles genome provides a near-complete catalog of enzyme families that play an important role in the catabolism of xenobiotics. Furthermore, the availability of SNPs in these genes will facilitate monitoring of the frequency and spread of resistance alleles and efforts to locate the major loci associated with resistance to DDT and pyrethroids.



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Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91%of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency ("dual haplotypes") in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.

The mosquito is both an elegant, exquisitely adapted organism and a scourge of humanity. The principal mosquito-borne human illnesses of malaria, filariasis, dengue, and yellow fever are at this time almost exclusively restricted to the tropics. Malaria, the most important parasitic disease in the world, is thought to be responsible for 500 million cases of illness and up to 2.7 million deaths annually, more than 90% of which occur in sub-Saharan Africa.

Anopheles gambiae is the major vector of Plasmodium falciparum in Africa and is one of the most efficient malaria vectors in the world. Its blood meals come almost exclusively from humans, its larvae develop in temporary bodies of water produced by human activities (e.g., agricultural irrigation or flooded human or domestic animal footprints), and adults rest primarily in human dwellings. During the 1950s and early 1960s, the World Health Organization (WHO) malaria eradication campaign succeeded in eradicating malaria from Europe and sharply reduced its prevalence in many other parts of the world, primarily through programs that combined mosquito control with antimalarial drugs such as chloroquine. Sub-Saharan Africa, for the most part, did not benefit from the malaria eradication program, but the widespread availability of chloroquine and other affordable antimalarial drugs no doubt helped to control malaria mortality and morbidity. Unfortunately, with the appearance of chloroquine-resistant malaria parasites and the development of resistance of mosquitoes to the insecticides used to control disease transmission, malaria in Africa is again on the rise. Even control programs based on insecticide-impregnated bed nets, now widely advocated by WHO, are threatened by the development of insecticide resistance in A. gambiae and other vectors. New malaria control techniques are urgently needed in sub-Saharan Africa, and to meet this challenge we must grasp both the ecological and molecular complexities of the mosquito. The International Anopheles gambiae Genome Project has been undertaken with the hope that the sequence presented here will serve as a valuable molecular entomology resource, leading ultimately to effective intervention in the transmission of malaria and perhaps other mosquito-borne diseases.
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Dan