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Sequencing Projects Provide New Clues About Malaria Parasites

NEW YORK (GenomeWeb News) – Two international research teams reported today that they have sequenced the genomes of malaria parasites that infect humans and monkeys.
In a pair of papers appearing online today in Nature, researchers described their efforts to sequence and begin deciphering the genomes of Plasmodium knowlesi, a malaria parasite infecting kra monkeys that’s increasingly found in human malaria cases in parts of Asia, and P. vivax, the parasite causing the bulk of human malaria infections outside of Africa. Together, the new papers are providing new insights into malaria biology — and giving researchers the opportunity to begin comparing the genomes of several malaria culprits.
“The most important thing is [the genomes’] availability,” Elizabeth Winzeler, a cell biologist affiliated with the Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation, who was not involved in either study, told GenomeWeb Daily News. “It sets such an important foundation for future work.”
Winzeler, who penned a review accompanying today’s Nature articles, said that by comparing the genomes of different Plasmodium species, it should be possible to root out core set of genes essential to parasite life. Ultimately, researchers hope to uncover targets that could help them combat the disease with new drugs or vaccines.
Plasmodium parasites, tiny protozoa carried by mosquitoes, cause an estimated 515 million human malaria cases each year. The disease, which is characterized by fever, chills, headache, nausea, and vomiting, can lead to long-term learning deficits or even death.
Six years ago, a team of researchers reported that they had sequenced the genome of P. falciparum, the parasite causing the deadliest form of malaria.
But P. falciparum is not alone in causing human disease. While that species is most common in Africa, another, called P. vivax, causes roughly a quarter of all malaria cases and is the prevalent human pathogen in Asia and the Americas. P. ovale and P. malariae have also been linked to human disease.
More recently, it’s been shown that P. knowlesi, a species known to infect monkeys, can also infect humans, leading many to argue that P. knowlesi is an under-appreciated cause of human malaria. P. knowlesi is “increasingly being recognized” in human infections, Arnab Pain, a researcher at the Wellcome Trust Sanger Institute, told GenomeWeb Daily News.
Pain is lead author on the paper describing the P. knowlesi genome sequencing effort. He and his colleagues sequenced the 23.5 million base P. knowlesi genome to eight times coverage using whole-genome shotgun Sanger sequencing and subsequently identified 5,188 protein-coding genes. Some 80 percent of these had known orthologues in P. falciparum and the newly sequenced P. vivax, underscoring the notion that P. knowlesi could serve as a useful model organism for the yet-unculturable P. vivax.
The genome sequence also yielded quite a bit of unexpected information, Pain said. For instance, the researchers discovered that P. knowlesi is capable of molecular mimicry. It apparently employs proteins that are identical to human host proteins to evade the human immune system. “This kind of identical host match is the first of its kind in any malaria parasite,” Pain said.
They also found that genes involved in antigen variation and host evasion tend to be dispersed throughout the P. knowlesi genome. That’s distinct from other Plasmodium species, which typically concentrate these genes at the ends of chromosomes in sub-telomeric regions.
Meanwhile, a research team led by investigators at the Institute for Genomic Research, the J. Craig Venter Institute, and New York University focused their efforts on P. vivax, the second most common cause of malaria in humans. P. vivax was the “obvious next choice to sequence,” lead author Jane Carlton, a parasitologist at New York University’s Langone Medical Center, told GenomeWeb Daily News, since it has not yet been cultured in the lab, and is relatively poorly understood.  
Although P. vivax does not typically cause death, she added, it can cause severe symptoms — in some cases, more severe than those associated with P. falciparum. In addition, the parasite can remain dormant in the liver and cause symptoms months or years after initial infection.
For this paper, the researchers sequenced the 26.8 million base pair P. vivax genome to ten times coverage using whole-genome shotgun Sanger sequencing. Analyzing the P. vivax genome was challenging, Carlton noted, because it has an isochore-like structure with G/C-rich regions as well as A/T-rich telomeric regions.
Within the P. vivax genome, the researchers found that gene families involved in immune response and the production of proteins found on the surface of red blood cells were larger than those in other Plasmodium species — gene amplification that may help the parasite evade host immune systems.
The researchers also identified eight gene families that are unique to P. vivax and pinpointed 160 microsatellites in the P. vivax genome. These microsatellites are currently being used for population and diversity studies and association mapping of drug resistance, Carlton said.
Next, the team compared the genomes of P. vivax, P. knowlesi, P. falciparum, and P. yoelii yoelii, a rodent parasite whose genome sequence was published in 2002. In general, they found that these Plasmodium genomes tend to be between 23 megabases and 27 megabases and contain roughly 5,500 genes. Unexpectedly, some 77 percent of these genes are orthologous between all four species. In addition, the researchers noted, the parasites share many genes with similar gene structure.
Notably, P. vivax seems to share a number of metabolic pathways with P. falciparum, the authors noted, suggesting it may be possible to target P. vivax with some of the same drugs and vaccine candidates currently being developed to combat P. falciparum.
At the moment, the researchers are working with collaborators at the Broad Institute to sequence six additional P. vivax strains from Brazil, Mauritania, India, Indonesia, Papua New Guinea, and North Korea, Carlton said. This sequencing effort will likely rely on a combination of Sanger sequencing and next-generation sequencing, such as Roche 454’s GS FLX platform.
Winzeler and the researchers involved in the studies expressed enthusiasm about applying the information gleaned from the new malaria genomes. “Although new, licensed therapies may not yet have resulted from genome-dependent experiments, they have produced a wealth of new observations about the basic biology of malaria parasites,” Winzeler wrote, “and it is likely that these will eventually lead to new therapeutic approaches.”
Even so, both Winzeler and Carlton noted that malaria eradication poses many challenges. For instance, while there are likely several new drugs for P. falciparum in the pipeline, Winzeler said, both distributing drugs within Africa and getting rid of mosquitoes that carry the parasite remain difficult.
And because the parasites can remain dormant in the liver and re-appear after months or even years, eradicating P. vivax presents a host of other problems, Winzeler said.
Carlton expressed similar concerns about trouncing the robust species. “It’s going to be an even bigger challenge for vivax.”
In the future, Carlton said, it will be important to do experiments aimed at characterizing P. vivax’s dormant stage. That will likely include gene expression and proteomic studies, as well as candidate gene experiments, she said, adding that the team has already identified a few candidate genes that could potentially have a role in dormancy.
For their part, Sanger researchers and their collaborators are currently working on unraveling the genetic sequence of the remaining human malarial parasites, P. ovale and P. malariae.
Sequence data for this and other Plasmodium sequencing projects is available through the PlasmoDB database. There are also genome-scale reagents such as a long-oligo array and a complete clone set of the genome available at National Institute of Allergy and Infectious Disease-funded repositories MR4 and PFGRC.

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