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Malaria Parasite Re-Sequencing Uncovers Possible Drug Resistance Genes

By Andrea Anderson

NEW YORK (GenomeWeb News) – By re-sequencing and analyzing the genome of Plasmodium vivax directly from an infected patient's blood, an international research team has identified several genes that appear to be under selection — and may contribute to drug resistance — in the malaria-causing parasite.

The group analyzed the genome of a malaria isolate from Peru using a combination of high-throughput whole-genome sequencing and tiling array analyses. In so doing, they not only identified more than 18,000 SNPs compared to a previously sequenced reference genome, but also detected a handful of genes that appear to be possible drug resistance genes in the P. vivax parasite.

"We show here how microarray-based polymorphism detection and whole-genome sequencing can be used to create genome-wide maps of genetic diversity in P. vivax and how this may lead to new drug-resistant candidate genes, new vaccine candidates, and new tools in developing treatment policy," senior author Elizabeth Winzeler, a cell biology and genomics researcher affiliated with the Scripps Research Institute and Novartis Research Foundation's Genomics Institute, and her co-authors wrote in the Proceedings of the National Academy of Sciences.

The P. vivax parasite, which is mainly found in Mexico, South America, India, and Asia, has been implicated in 25 to 40 percent of all malaria cases, Winzeler and her colleagues explained. Even so, relatively little research has been done on the parasite, in part because it is difficult to culture.

Consequently, they noted, the P. vivax reference genome was generated from an isolate collected in Salvador in 1970 that had been adapted to grow in primates in order to get enough DNA for sequencing.

"It's been fairly difficult to work on Plasmodium vivax, even though it's a huge, worldwide health problem," Winzeler told GenomeWeb Daily News. On the other hand, she noted, P. falciparum, which is largely confined to Africa, is thought to be a more lethal malaria parasite, but is also easily cultured in the lab.

For the current study, Winzeler and her co-workers attempted to overcome this problem by trying to sequence DNA directly from a patient blood sample that had been filtered over a white blood cell filter to remove as much human genetic material as possible.

Using whole-genome amplification on the Illumina Genome Analyzer, they were able to sequence the 26.8 million base genome of a P. vivax strain that had been isolated from a Peruvian patient in 2007 to about 30 times coverage, on average.

Through comparisons with the P. vivax reference genome, the researchers uncovered 18,261 SNPs. So far, they have confirmed nearly 6,300 of these using custom Affymetrix whole-genome tiling arrays based on the P. vivax reference genome. As reported for P. falciparum, their analysis suggests that much of the genetic variation in the genome occurs in multi-gene families.

By comparing ratios of non-synonymous to synonymous variants within the newly sequenced genome, the team was also able to gain new clues about which genes are under selection and may be involved in drug resistance in the parasite.

In particular, that analysis pointed to a transporter gene known as multi-drug resistance protein or pvmrp1 — a candidate gene that's also been linked to potential drug resistance mechanisms in the P. falciparum parasite.

"We found additional support for our hypothesis that this might be an interesting gene, but we really need to do more studies," Winzeler noted.

Their search for genes under selection also pointed to transcription factors in the AP2 family as potential drug resistance candidate genes.

Moreover, Winzeler explained, having the ability to sequence P. vivax from patient samples suggests it should be possible to streamline this process in order to do whole-genome association studies of the parasite.

"Developing tools for studying genetic diversity directly from field samples in P. vivax is critical because it allows for discovery and monitoring of genes involved in drug resistance as well as for identifying potential vaccine candidates," the researchers wrote.

In the near future, the team plans to apply their strategies to not only get a more complete picture of malaria genetics, but also to continue rooting out regions of the genome with roles in resistance to anti-malarial drugs.

"We would like to initiate projects where we do more detailed phenotyping of the parasites," Winzeler said, explaining that this may involve clinical trials in which patients are sampled before and after treatment to look for shared genetic features in resistant parasites.

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