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The Microbial Sequencing Center at the Ó³»­´«Ã½ has been awarded funding from the National Institute of Allergy and Infectious Diseases (NIAID) to sequence two isolates of Plasmodium falciparum, the leading disease-causing agent of malaria in humans.

Malaria is one of the major infectious diseases in the world today, with 300-500 million new cases each year and 1-2 million deaths. Although malaria has been eradicated from many developed countries, the disease remains a major health problem in developing countries in tropical and subtropical parts of the world. In addition, it is making a dramatic comeback in areas where it was once eliminated or suppressed. The reasons for malaria's changing disease landscape are complex and include antigenic variation in the parasite and the emergence of drug-resistant organisms.

"Malaria is a very important disease to understand," says Dyann Wirth, who co-directs the Infectious Disease Initiative at the Ó³»­´«Ã½ with Jon Clardy, and directs the Harvard Malaria Initiative in the Department of Immunology and Infectious Disease at Harvard School of Public Health. "Applying genomic approaches developed for human to a parasite with a genome 1/100th the size of the human genome gives us an enormous opportunity to gain new insights into parasite biology and discover important properties associated with disease."

The genetic variability of P. falciparum underlies both its transmission success and its ability to thwart efforts to control it. In particular, resistance to antimalarial drugs arises rapidly in the parasite through mutations in its genome. Thus it is important to gain a basic understanding of the degree and type of genetic variability by sequencing several different strains or "isolates" and comparing the results.

Scientists at Ó³»­´«Ã½ have begun sequencing P. falciparum isolates Dd2, originating from Indochina, and HB3, from Honduras, and will begin extensive comparative projects based on these data. Of particular interest in choosing these two isolates is the potential for understanding their difference in known drug resistance and several other biological properties. The primary value in identifying differences in these individuals at the genome level will be the ability to correlate that knowledge with their known phenotypic differences, including the progeny of their genetic cross.

Furthermore, data resulting from this research will seed genotyping in a larger set of strains that will become part of a haplotype mapping project for malaria. "The Plasmodium HapMap for Malaria is an exciting new initiative at the Ó³»­´«Ã½ in collaboration with a consortium of investigators worldwide," says Wirth.

Comparative Plasmodium genomic efforts at the Ó³»­´«Ã½ will not only involve Dd2 and HB3, but also many other strains and species that have already been sequenced or that are underway at the Ó³»­´«Ã½ and other institutions. The Plasmodium species for which sequences will ultimately be available are clustered in three groups in the evolutionary tree, which will help scientists answer meaningful questions about how the Plasmodium genome has evolved.

"One of the first things we are interested in looking at is potential correlates of virulence and drug resistance," says James Galagan, Associate Director in charge of Microbial Sequence Analysis at Ó³»­´«Ã½ who is leading the comparative genome analysis. His group will study the biology of the Plasmodium parasite with regard to virulence and infectivity by looking closely at the ends of chromosomes, because these regions evolve rapidly in all organisms.

"Comparative analysis is a powerful method that allows us to use evolution to identify the important similarities and differences between organisms," says Galagan. "This is especially powerful when combined with functional and clinical data."

"Ultimately," says Wirth, "these integrated genomic approaches will provide new insights into the biology of Plasmodium that will translate into advances to combat malaria worldwide."

The Ó³»­´«Ã½'s Microbial Sequencing Center is a five-year, $75 million project led by Bruce Birren and funded by NIAID, part of NIH, whose goal is to transform biodefense and infectious disease research by creating resources for DNA sequencing and comparative genome analysis.