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European Team Unravels Genetic Basis of Mosquito Resistance to Malaria

NEW YORK (GenomeWeb News) – Genetic variants in a lone gene appear to mediate the Anopheles gambiae mosquito's resistance to at least one malarial parasite species, according to a paper appearing online today in Science.

A team of German and French researchers assessed malaria sensitive, resistant, and intermediate A. gambiae mosquitoes using several techniques, including a genome-wide association study for resistance, targeted re-sequencing and an approach called reciprocal allele-specific RNA interference, or rasRNAi. In the process, they found variants in one gene — called antiparasitic thioester-containing protein 1, or TEP1 — that apparently governs malaria resistance.

Senior author Lars Steinmetz, joint unit coordinator for the European Molecular Biology Laboratory's Genome Biology unit, told GenomeWeb Daily News that the rasRNAi approach itself is exciting because it allows the application of RNAi in all organisms with complex traits down to the gene level.

A. gambiae mosquitoes are the primary vector for the parasite Plasmodium falciparum in Africa and other parts of the world. That's a concern since P. falciparum is not only linked to the most severe malaria cases but also is the most common cause of malaria in Africa and other parts of the world.

Even so, not all A. gambiae mosquitoes are equally susceptible to the parasite. Past studies have shown that it's possible to select for mosquito strains that resist P. falciparum, although the genetics underlying this resistance are poorly characterized.

To explore this further, Steinmetz and his team looked for genetic features that mediate resistance to a related malaria parasite called P. berghei, which infects rodents.

After crossing malaria-resistant and -susceptible mosquito strains, the researchers let the female mosquito offspring feed on mice infected with a fluorescently tagged version of P. berghei. They then looked at which of the mosquitoes had living or dead parasites in their gut after a week or so.

Whereas mosquitoes from the resistant parental strains contained only dead parasites, and mosquitoes from susceptible strains contained only living parasites, the 111 first-generation offspring and 402 second-generation offspring guts harbored both living and dead parasites. The pattern of resistance inheritance was complex, the researchers noted, and inconsistent with Mendelian inheritance.

When the team genotyped 39 markers sprinkled across the genome in 206 second-generation mosquito offspring with the most pronounced P. berghei resistance or susceptibility profiles, they found a 19 million base region on chromosome 3 that was linked to this resistance. Their subsequent analyses suggest this region house some 975 genes. Of these, the team noted, roughly 35 have previously been classified as immune-related genes, including TEP1, a polymorphic gene coding for a protein that binds P. berghei.

Indeed, the researchers identified several variants in TEP1 when they sequenced and compared the gene in a handful of resistant and susceptible parental mosquitoes.

"There are a large number of polymorphisms between the two versions, the sensitive and resistant" TEP1 gene, Steinmetz said.

In order to determine which of these variants related to malaria resistance, the team used the rasRNAi approach to individually silence the resistant and sensitive TEP1 alleles in the first-generation offspring.

Allele-specific RNA interference has been used before, Steinmetz explained. For instance, in 2004, University of Massachusetts researcher Zuoshang Xu was awarded a patent for allele-specific RNAi related to inhibiting the expression of mutant alleles in human diseases in which a wild type and mutant copy of a gene is present.

But Steinmetz and his colleagues extended the approach, focusing on both alleles — a reciprocal method that Steinmetz says facilitates the dissection of complex genetic traits.

They found that in the absence of the allele inherited from the resistant parent, mosquitoes were more malaria sensitive. In contrast, when the offspring were missing the allele inherited from the sensitive parent they were more malaria resistant.

In all, the team identified three TEP1 alleles that contribute to malaria sensitivity or resistance, though they say other alleles are likely involved as well

While it remains to be tested whether TEP1 variation has a similar effect on mosquito sensitivity and resistance to human malaria parasites such as P. falciparum, Steinmetz cautioned, he and his team hope that identifying these alleles could eventually help prevent and control human malaria transmission.

For instance, Steinmetz noted that allelic variation in TEP1 might become a useful marker for mapping regions where mosquitoes are resistant or susceptible to malaria. If so, malaria prevention measures could be specifically targeted to areas harboring malaria-sensitive mosquitoes, which are more likely to transmit the parasite to humans.

The researchers also believe the rasRNAi method will prove useful in other species. For example, Steinmetz said his team is currently applying rasRNAi to studies of human cell lines.

"The successful application of rasRNAi in Anopheles suggests that it could also be applied to other organisms where RNAi is feasible to dissect complex phenotypes to the level of individual quantitative trait alleles," the team wrote.

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