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Genomic Strategies Uncover Genes behind Malaria Drug Resistance

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online last night in PLoS Genetics, researchers from the US, Senegal, and Nigeria reported that they have successfully used natural selection signals, along with a genome-wide association approach, to find genes that seem to influence how the malaria parasite Plasmodium falciparum dodges drug treatments.

The team, led by investigators at the Broad Institute and Harvard University, came up with a high-density genotyping array that they used to test dozens of culture-adapted P. falciparum parasites collected in Africa, Asia, and the Americas. Their analysis uncovered 20 loci with genetic diversity patterns consistent with relatively recent natural selection. Meanwhile a GWAS looking for variants linked to drug resistance pointed to 11 potential resistance genes in the parasite.

The resistance role for one of these — an apparent resistance gene called PF10_0355 that contains several SNPs associated with halofantrine resistance — was supported by the team's follow-up functional studies. They found that elevated expression of the gene coincides with muted malaria parasite sensitivity to not only halofantrine, but also to mefloquine and lumefantrine.

"[T]his study confirms that we can use genome-wide approaches to identify clinically relevant genes and demonstrates through functional testing that at least one of these candidate genes is indeed involved in antimalarial drug resistance," corresponding author Pardis Sabeti, an organismic and evolutionary biology researcher affiliated with the Broad Institute and Harvard, and her co-authors wrote.

In the first phase of the study, the team used their high-density genotyping arrays to assess 57 malaria parasites collected on three continents at some 17,582 sites across the genome, looking for natural selection signals from the SNP data.

A subsequent GWAS relied on genotyping of 7,437 SNPs to look for P. falciparum loci linked to drug resistance in 50 culture-adapted parasites that had been assayed for resistance to 13 antimalarial drugs.

Together, the approaches turned up a handful of possible resistance genes, including the functionally validated gene PF10_0355.

By continuing to look for resistance genes using these and other genomic approaches, researchers hope to find biological clues for combating malaria parasites more effectively.

"Once we understand the processes used by the parasite to avoid the effects of the antimalarial treatment, scientists can develop new drugs that circumvent the strategies employed by the drug-resistant malaria parasite," co-senior author Sarah Volkman, a researcher at the Harvard School of Public Health, said in a statement.

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