The Institute for Genomic Research
That focus on the parasites' complex life cycle is helping researchers understand when different genes switch on and off as the pathogens metamorphose through seven different life stages. In turn, that molecular-level data may benefit biomedical scientists who are identifying new targets for vaccines that would impede the parasite during stages when it is particularly vulnerable to intervention.
"We hope this project will help vaccine researchers find the best targets against malaria," says scientist Neil Hall, the first author of the paper that appears in the January 7th issue of Science. "The study's findings will help scientists identify parasite genes that are interacting with the host as well as new gene targets for vaccines that aim to prevent parasite transmission in the mosquito."
The study highlights the genes in four malarial species that evolve rapidly because of "selective pressures" in the stages of their life cycles in their mosquito vectors and in their mammalian hosts. Malaria parasites undergo three stages in their mosquito vectors, three stages in their vertebrate hosts and a sexual development stage during which the parasite is transmitted between vector and host.
The Science paper represents the culmination of four years of cooperative work by scientists at several research institutes, including: the Wellcome Trust Sanger Institute in the U.K., where the sequencing and genome annotation was performed on two species of rodent malaria (Plasmodium chabaudi and P. berghei); the University of Leiden in the Netherlands and Imperial College in England, where scientists carried out gene expression studies; and The Institute for Genomic Research (TIGR), in Maryland, where scientists did a comparative analysis of the two draft genomes with those of the first rodent malaria parasite to be sequenced, Plasmodium yoelii.
The first author of the paper is Hall, a TIGR Assistant Investigator who did most of his work on this project while in his previous position as a bioinformatics scientist at Sanger. He was also the first author of the 2002 study led by scientists at TIGR, Sanger, and Stanford University that presented the complete genome of Plasmodium falciparum, the deadliest human malarial parasite.
Hall says the Science paper is important because:
Hall's group identified the gene regulation by comparing the genes expressed in the sexual stage transcriptome with the proteomes of both the sexual stage and a developmental stage in the mosquito. Several genes were identified for which transcripts were detected in the sexual stage but with protein products specific to the mosquito stage, indicating delayed translation of transcripts from these genes.
Hall says that gene-regulation motif "is particularly interesting because these proteins, expressed early in the mosquito, are the target of transmission-blocking vaccines" that is, vaccines which raise antibodies that attack the parasite in the vector. (Such antibodies are in the "blood meal" and still work for an hour or so after the mosquito bites).
Another TIGR scientist who played an important role in the project is Associate Investigator Jane Carlton, who had led the sequencing of P. yoelii. At TIGR, Carlton constructed a composite of all three rodent genome sequences (P. yoelii, P. berghei, P. chabaudi) by aligning them against the P. falciparum genome to create a whole-genome synteny map of the four species. In collaboration with Leiden University researchers, Carlton's group was then able to generate maps that compare the degrees of similarity among genes on P. falciparum chromosomes and its rodent-malaria counterparts.
"The paper is significant on many levels, including the integration of draft genome sequence data with microarray and protein expression data," says Carlton. "This project also shows the power of collaboration between international institutes with different areas of expertise. It was remarkably productive collaboration."
The Plasmodium study was sponsored by The Wellcome Trust, the European Union's research directorate, and the U.S. National Institutes of Health.
The Institute for Genomic Research (TIGR) is a not-for-profit research institute based in Rockville, Maryland. TIGR, which sequenced the first complete genome of a free-living organism in 1995, has been at the forefront of the genomic revolution since the institute was founded in 1992. TIGR conducts research involving the structural, functional, and comparative analysis of genomes and gene products in viruses, bacteria, archaea, and eukaryotes.
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