High-density genotyping and genome-wide association studies were used.
Scientists carrying out genotyping studies on malaria parasites have identified a new drug resistance gene that decreases the parasite’s sensitivity to halofantrine, mefloquine, and lumefanrine but not to structurally unrelated antimalarials.
The Harvard School of Public Health-led team used a high-density genotyping array to evaluate over 17,000 SNPs in 57 culture-adapted parasites from different continents. They then carried out a genome-wide association study (GWAS) to identify loci correlating with resistance to 13 antimalarials.
The results of this approach highlighted a number of already known and new loci. Functional studies in malaria parasites subsequently confirmed that overexpression of a gene at one identified locus, PF10_0355, was associated with resistance to the three antimalarial drugs. The locus codes for a putative erythrocyte membrane protein that is characterized by high genetic diversity and was found to contain multiple SNPs associated wtih halofantrine resistance.
Harvard senior research scientist Sarah Volkman, Ph.D., and colleagues claim that beyond identifying the new drug resistance locus, their research illustrates the utility of genome-wide association studies for discovering gene function in Plasmodium falciparum. The results are published in PLoS Genetics in a paper titled “Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum.”
The researchers in addition suggest that the two types of analyses used to mine the genetic basis of adaptation in Plasmodium falciparum are complementary. Scanning for selected loci permits an unbiased search for unknown adaptive changes but provides little information about the processes at work. Genome-wide association studies provide a more focused look at one easily identified (and clinically critical) adaptive phenotype.