Carvalho_2005

Carvalho_2005 - Curr. Issues Mol. Biol. 7: 39-56. Online...

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Teresa Gil Carvalho and Robert Ménard* Unité de Biologie et Génétique du Paludisme, Institut Pasteur, 25 Rue du Dr Roux, 75724 Paris Cedex 15, France Abstract Genome manipulation, the primary tool for assigning function to sequence, will be essential for understanding Plasmodium biology and malaria pathogenesis in molecular terms. The ± rst success in transfecting Plasmodium was reported almost ten years ago. Gene- targeting studies have since ² ourished, as Plasmodium is haploid and integrates DNA only by homologous recombination. These studies have shed new light on the function of many proteins, including vaccine candidates and drug resistance factors. However, many essential proteins, including those involved in parasite invasion of erythrocytes, cannot be characterized in the absence of conditional mutagenesis. Proteins also cannot be identi± ed on a functional basis as random DNA integration has not been achieved. We overview here the ways in which the Plasmodium genome can be manipulated. We also point to the tools that should be established if our goal is to address parasite infectivity in a systematic way and to conduct re± ned structure-function analysis of selected products. Introduction It is safe to predict that the wealth of information revealed by the sequence of the Plasmodium falciparum genome will bene± t many areas of malaria research (Waters and Janse, 2004). New drug targets will be identi± ed by capitalizing on the comprehensive view of parasite metabolism, as was already done to demonstrate the anti- malarial activities of fosmidomycin and triclosan (Jomaa et al ., 1999; Surolia and Surolia, 2001). Another much anticipated impact of the genome sequence is on vaccine development, via the formulation of new ‘vaccinomic’ approaches (Hoffman et al 1998; 2002). Comparative genomics will soon be possible as the genome sequence of more Plasmodium species and other Apicomplexa is completed, and will provide insights into the evolution of these protozoan parasites and adaptation to their hosts. To what extent will the sequence help us to understand Plasmodium biology? Encompassing 14 chromosomes, the ~25-megabase Plasmodium genome is predicted to encode ~5,000 genes. Apicomplexa are part of one of the most ancient eukaryotic lineages, phylogenetically distant from the model organisms already sequenced. They have unique structural features and have evolved distinct solutions to basic problems; for example they divide by multiple ± ssion, locomote by gliding and induce the formation of new membrane compartments in the host cell. Not surprisingly, the proportion of Plasmodium products that have homologs in other organisms is the lowest among sequenced genomes. Annotation of P. falciparum chromosome 2 (Gardner et al ., 1998) and 3 (Bowman et al ., 1999) left about two-thirds of the predicted genes without function, either having no detectable homolog or a Plasmodium/ Apicomplexa-speci± c homolog for which we have no functional information. Function was tentatively assigned
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Carvalho_2005 - Curr. Issues Mol. Biol. 7: 39-56. Online...

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