This project proposes to sequence about a third (greater than 10 Mb) of the Leishmania genome as part of the international Leishmania Genome Network (LGN) effort to sequence the entire genome within the grant period. Leishmania was selected for this project since it is an excellent model eukaryotic pathogen which has convenient genomic and biological characteristics and is experimentally useful. This laboratory will generate sequence ready maps of several Leishmania chromosomes by extending the low resolution map that has been generated from cosmid fingerprinting and genomic mapping. The map of chromosome 1 will be compared between two Leishmania species to establish the basis for chromosome size differences and examine conservation of gene order. The investigators will determine and analyze the sequence of the mapped chromosomes. Sequencing of chromosome 1 is already nearing completion. Two of the smallest (1 and 4), two of the largest (34 and 29), and two intermediated (7 and 8) chromosomes will be sequenced, in that order, to provide insight into the macro-organization of the genome. Additional chromosomes will sequenced in an order that is determined within the LGN. An informatics system will utilized to support this effort and contribute to the global LGN effort. This system will support process management, mapping, sequencing, sequence analysis, data exchange within the LGN, and archival of data in public databases. All software will be tightly integrated with a mapping and sequencing database which will be the focal point for data access, analysis, and exchange among collaborators. The project will generate a valuable resource of data and materials that will lay the foundation for the development of novel chemotherapeutic and immunological approaches to parasite control. It will contribute to the identification of genes for candidate vaccine antigens, diagnostics and drug targets, as well as those with roles in pathogenesis, invasion of host macrophages, immune evasion and immunomodulation. It will also identify genes for fundamentally important biological functions. The very early divergence of the kinetoplastids in the eukaryotic lineage will identify conserved ancient motifs and variable domains which will aid protein structure/function studies. The investigators anticipate that this project will result in the first complete genomic sequence of a eukaryotic pathogen and the resultant data will provide important insights into a wide variety of disease-related and fundamental phenomena that may lead to novel preventative, diagnostic, and therapeutic strategies.
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