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Genome sequence of the human malaria parasite Plasmodium falciparum

Secrets in the mosquito and parasite genomes explored.

The parasite took longer to sequence than its carrier the mosquito. Credit: © WHO/S.Stammers

Man is both essential vehicle and easy victim for the malaria injected by mosquitoes. But that may be about to change: "For the first time," says genome researcher Malcolm Gardner, "we have the genomes of the three organisms in this life cycle."

After six years, Gardner and an international team have pieced together the DNA sequence of the tiny parasite Plasmodium falciparum that causes the majority of human malaria. Simultaneously, a second team has completed that of its carrier, the mosquito Anopheles gambiae. The third piece of the jigsaw, the human genome, was completed two years ago.

No one pretends that knowing these strings of DNA will stamp out the disease tomorrow. "We're not claiming this is it for malaria," says Gardner, of The Institute for Genomic Research in Rockville, Maryland.

What it does do is catalogue genes that could be targeted by future drugs or vaccines to eliminate the parasite, or by insecticides to crush the insect. These leads are needed to tackle the many strains of Plasmodium resistant to current drugs such as chloroquine, or mosquitoes resistant to widely used insecticides. "It's going to empower dozens of labs around the world," predicts Gardner.

Long and short of it

These days, six years is a long time in genome sequencing - a draft of the mouse sequence was readied in months. Part of the problem with the parasite was that over 80 % of its genome features just two of DNA's four chemical building blocks, which presented a major challenge to sequencing machines and computers. "Many people told us it was impossible," says Gardner.

But now it is done, the 5,300 genes in P. falciparum's genome are expected to contain an array of metabolic enzymes that could be potential drug targets. Vaccine researchers too, who are already evaluating about 30 promising proteins, now have hundreds more. "They are drinking from a fire hose," says Gardner.

The parasite researchers have already analysed the proteins made by P. falciparum during the various stages of its lifecycle. They have also sequenced the genome of the Plasmodium species that infects rats, P. yoelii yoelii, which will aid the rodents' use as an animal model of the disease.

The mosquito's genome, on the other hand, was a quick project - sequencing took only about three months. Nevertheless, "it's been high stress", says Robert Holt of Celera Genomics in Rockville, Maryland, where the bulk of the sequencing was carried out.

It's been high stress Robert Holt , Celera Genomics

Out of the mosquito's 14,000 genes, Holt's collaboration has catalogued those involved in breaking down toxic substances such as insecticides. Disrupting this process could offer a way to tackle insecticide-resistant mosquitoes.

Genes for the mosquito's immune system, which are involved in the fight against the parasite dwelling in the insect's gut and salivary glands, have also been indexed. Increasing this natural immune reaction could help to beat the parasite. "It's a tall order but within the realms of possibility," says Fotis Kafatos of the European Molecular Biology Laboratory in Heidelberg, Germany, one of the collaboration's leaders.

The researchers also revealed a novel set of smell receptors that might explain A. gambiae's particular liking for human blood. These might be used to screen for new insect repellents, suggests Holt.

Both teams agree that lining up human, mosquito and parasite genomes will reveal how each responds to the other - and the vulnerable points that may be exploited. "Everyone's really pumped about it," says Holt.

References

  1. Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature, 419, 498 - 511, (2002).

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  2. Holt, R. et al. The genome sequence of the malaria mosquito Anopheles gambiae. Science, 298, 129 - 149, (2002).

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Genome sequence of the human malaria parasite Plasmodium falciparum. Nature (2002). https://doi.org/10.1038/news021001-4

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