"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 compa
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: * The study takes an
"evolutionary approach" to exploring how the Plasmodium genome has
evolved. By comparing four sequenced genomes (the human malaria P.
falciparum and the rodent malarias P. yoelii, P. chabaudi and P.
berghei), the scientists found that the major differences between the
malarial species are found in the virulence factors (which are at the
chromosome ends) while the "housekeeping" genes are almost totally
unchanged. * Researchers showed that the parasite genes evolve most
rapidly when they are expressed in the mammal hosts (human/mouse). That
may represent a mechanism by the parasites to repulse the attack of the
host's immune system. * For the first time, scientists were able to
study the protein expression of the parasite in the mosquito vector.
Researchers hope this will shed light on how the mosquito and parasite
interact, and perhaps will lead to new ways of controlling the parasite
in the vector. * Hall and scientists in Leiden identified evidence of
an unusual method of gene regulation (called post transcriptional
regulation) at the transition between the vertebrate host and the
mosquito. That motif regulates proteins that are switched on as the
parasite enters the mosquito.
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
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
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."
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