This project presents a unique multidisciplinary approach combining the expertise of Hartl, Wirth and Day in evolutionary genetics, genomics and molecular epidemiology to examine several hypotheses concerning the genomic diversity of the important human pathogen, Plasmodium falciparum. The project will exploit information from The Malaria Genome Project and make use of a well characterized bank of parasite isolates from diverse geographic origins to (1) verify an important prior report of extraordinary lack of synonymous polymorphisms in P. falciparum; and (2) to test the controversial """"""""Malaria's Eve"""""""" hypothesis proposing that a demographic or selective sweep of a single parasite genome could account for the lack of synonymous polymorphisms; and (3) to test the hypothesis that changes in gene regulation, rather than protein structure, drive evolutionary adaptation; and (4) to estimate population genetic parameters Nu (mutation parameter) and N's (selection intensity) to assess parasite evolution; and (5) to examine the feasibility of a single nucleotide polymorphism (SNP) map of the P. falciparum genome. The experimental approach involves identifying (SNP) evolution in housekeeping genes, under no obvious selection for diversity, and analyzing sequence polymorphism data using Poisson random field theory. Sequence polymorphisms in 5' regulatory, coding and noncoding (introns) regions of 19 housekeeping genes on chromosomes 2 and 3 will be identified in a large set of well-characterized parasite isolates from Brazil, Thailand, Papua New Guinea (PNG) and Tanzania. These endemic areas differ in transmission intensity and measures of population structure as assessed by linkage disequilibrium analysis, inbreeding coefficients and the distribution of genotypes per person. Sequence information will be analyzed in the context of novel population genetic methods developed by Professor Hartl for description of genomic diversity of Escherichia coli and Drosophila melanogaster to address the above mentioned questions.
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