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International Team Publishes Malaria Parasite GWAS

NEW YORK (GenomeWeb News) – An international group of researchers has published the first genome-wide association study on the malaria parasite Plasmodium falciparum, looking for genes associated with antimalarial drug resistance and more.

The team used a custom microarray to assess nearly 200 culture adapted P. falciparum isolates from around the world. The research, which appeared online yesterday in Nature Genetics, identified clusters of P. falciparum that correspond to regions where the isolates were collected and uncovered recombination hotspots in the parasite's genome. In addition, the researchers narrowed in on a set of candidate genes involved in antimalarial drug response.

"We are seeing clear population structure," co-corresponding author Philip Awadalla, a pediatrics researcher at the University of Montreal, told GenomeWeb Daily News.

P. falciparum is one of several Plasmodium species capable of causing malaria in humans. But despite ongoing attempts to combat the disease, its resistance to a range of antimalarial drugs has stymied control efforts. Research aimed at genetically characterizing the parasite has been slow, the team noted, due to a lack of genetic tools and difficulty culturing the parasite in the lab.

In an effort to better understand P. falciparum genetic patterns, identify genes contributing to drug resistance, and get clues about new drug targets, Awadalla and his co-workers used a custom Affymetrix array targeting 3,354 SNPs to genotype 189 cultures that had been developed from 146 P. falciparum isolates collected in Asia, 26 isolates collected in Africa, 14 collected in America, and three collected in Papua New Guinea.

The SNPs interrogated by the array were selected based on re-sequencing studies and other research on genetic variation in P. falciparum and related malaria parasites by this team and other research groups, Awadalla explained.

The team found that the isolates fell into genetic clusters corresponding to the parts of the world where the parasites had been collected.

By comparing strains within each continent, they were also able to tease apart some fine structure differences within the parasite populations. For instance, their results showed separation between isolates collected in part of Cambodia compared with those found in the rest of the country or in Thailand.

They also detected recombination hot- and cold-spots in the parasite's genome, Awadalla noted, which seem to be conserved but vary in intensity between different P. falciparum populations. In general, the researchers reported, the parasite's five largest chromosomes tended to show less recombination than its nine smaller chromosomes.

In addition, the data helped the team gain insights into linkage disequilibrium patterns and haplotype structure within the P. falciparum genome as well as sites that appear to be under selection in the genomes of isolates from each part of the world sampled.

The researchers also did a set of experiments aimed at better understanding the P. falciparum parasite's response to seven different antimalarial drugs, including GWAS experiments identifying known and previously unidentified drug resistance candidate genes.

Although they saw drug resistance in all of the geographic regions sampled, they reported most isolates are still fairly sensitive to the drugs dihydroartemisinin and piperaquine. Still, the specific drug sensitivities varied depending on where the isolates had been collected. For instance, some isolates from Cambodia seem to be slightly more resistant to dihydroartemisinin and piperaquine.

Awadalla and his colleagues are currently using ABI SOLiD and Illumina's technology to do sequencing studies of P. falciparum in an effort to continue finding and characterizing rearrangements and recombination events in the genome. They are also continuing to collect new strains from around the world and are particularly keen to get samples from South and Central America.