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Team Determines Malaria Parasite Genomes, Diversity with DNA from Patient Samples

NEW YORK (GenomeWeb News) – Many of the same genetic variant alleles appear to be present in Plasmodium vivax malaria parasites from different parts of the world, according to a malaria parasite sequencing study appearing online in PLoS Neglected Tropical Diseases last night.

Researchers from the US, Cambodia, France, and Madagascar used high-throughput sequencing to sequence P. vivax genomes to average depths of about 70- to 400-fold with parasite DNA recovered from malaria patient blood samples. From the genome sequences of parasites infecting five individuals in Madagascar or Cambodia, combined with data on re-sequenced P. vivax strains, they managed to track down more than 80,000 SNPs in the malaria parasite's genome.

While some variants clustered by regions, the team saw many of the same allele patterns in P. vivax isolates collected from geographically distinct locales, hinting at extensive mixing between parasites from different places. Within all of the infected individuals tested, meanwhile, the investigators found multiple P. vivax strains, each with different haplotype profiles.

The P. vivax parasite's spread to different parts of the world is aided by the fact that it can remain dormant for long periods of time in infected individuals, co-senior author Peter Zimmerman, a genetics, biology, and global health researcher with Case Western Reserve University's Center for Global Health and Diseases, explained in a statement, noting that the P. vivax life cycle allows it to be a "microbial globe-trotter."

"If drug resistance arises, with modern travel, how long would it be before the resistance is spread over the world?" he added. "This data suggests it could quickly become a big problem."

Because the P. vivax parasite is extremely difficult to culture, relatively few genome-sequencing studies have been done on the parasite since its genome was first described in 2008. To get around problems with growing the parasite in the lab, some researchers have done whole-genome sequencing on P. vivax strains adapted for growth in monkeys.

In a study appearing in Nature Genetics last month, for example, American and Indian researchers used that strategy to sequence P. vivax isolates from three continents, identifying genetic patterns that pointed to higher genetic diversity in the relatively widespread P. vivax parasite compared to P. falciparum, a parasite found most often in Africa that causes a deadlier form of malaria.

Others have been working on ways to interrogate the parasite's genome directly from patient blood samples. For a 2010 study, for instance, another international research group sequenced P. vivax from a Peruvian patient's blood to an average coverage of around 30-fold, using that sequence data to help track down more than 18,000 P. vivax SNPs.

For the current study, Zimmerman and his colleagues used newer sequencing technologies to dramatically increase the coverage depth of genomes sequenced from patient samples. Two of the infected individuals came from Madagascar and three were in Cambodia.

Using the Illumina HiSeq 2000, they sequenced P. vivax DNA that had been isolated from five patients' red blood cells to depths of between 70- and 407-fold, on average. And the sequences they generated covered more than 90 percent of the P. vivax genome by at least 20 reads.

Researchers also sequenced a sixth P. vivax isolate, representing a South American strain known as Belem that had been grown in monkey hosts, and re-sequenced the strain used to generate the original P. vivax reference genome sequence.

By comparing the newly sequenced P. vivax genomes with one another, the investigators found 80,657 genetic variants, including some suspected of influencing the parasite's response and resistance to certain malaria drugs.

Blood cells from each of the patients tested contained multiple P. vivax strains, they reported. And strains from the same individuals tended to show distinct haplotype patterns, suggesting they weren't related to one another.

Even so, despite the fairly large selection of variants present in the genome, the alleles that turned up in the genomes of parasites from different parts of the world were surprisingly similar, the study authors explained. "[O]ur analysis of P. vivax genomes from three continents revealed allele sharing across continents and little evidence of local adaptations."

"One possible explanation for our observations is that the P. vivax population originated recently and dispersed rapidly across the world without major loss of diversity or much influence of natural selection," they noted. "Alternatively, allele sharing could be due to continuous gene flow in the present P. vivax population: P. vivax is now a cosmopolitan parasite that can be easily spread throughout the world by way of dormant hypnozoites."

In an effort to explore that possibility further — and to better understand P. vivax's spread and infection strategies — the researchers are now keen to use some of the SNP markers detected in the current study to test even more P. vivax samples.

"Our work provides the first report on genome-wide variation of this malaria parasite and provides the malaria research community with more than 80,000 genetic markers that can now be used for trait mapping or population monitoring," co-corresponding author David Serre, a researcher with the Cleveland Clinic Lerner Research Institute's Genomic Medicine Institute, said in a statement.

"This is a critical step to understand the biology of this parasite that cannot be studied in the laboratory yet affects millions of people each year," Serre added.

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