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Type of Document Dissertation Author Tan, John C Author's Email Address jtan1@nd.edu URN etd-09022008-121228 Title The Dynamic Structural Genome of Plasmodium falciparum Degree Doctor of Philosophy Department Biological Sciences Advisory Committee
Advisor Name Title Michael T. Ferdig Committee Chair Frank H. Collins Committee Co-Chair Jeanne Romero-Severson Committee Member Nora J. Besansky Committee Member Keywords
- copy number polymorphisms
- genomics
- VNTRs
- microarray genotyping
Date of Defense 2008-08-25 Availability restricted Abstract Plasmodium falciparum is the causative agent of the most severe and deadly formof malaria in humans causing significant amounts of human suffering. These
intracellular parasites are spread between vertebrate hosts by the bites of infected
Anopheles mosquitoes. A campaign to eradicate malaria initiated by the World Health
Organization in the 1950s had some initial success but the goal of global eradication was
eventually abandoned as it was determined to be unrealistic. Currently there is no
approved vaccine to combat malaria, and drug resistance of parasites to antimalarial
drugs is a real and growing concern.
Genome sequencing projects have been completed for humans, the mosquito
vector, and the causative parasite with the prospects and expectations of breakthroughs in
combating malaria. These genome sequences, in addition to being substantial technical
achievements, are significant and meaningful enabling resources of information. The
challenge to the research community is to devise useful applications, leading to
discoveries from this wealth of information.
The parasite has shown a remarkable ability to adapt to novel antimalarial drugs.
Microarrays – which have enabled by the information from sequencing projects – afford a global view of changes in the parasite over time and following selection pressures.
Depending on the target (RNA or DNA), this includes the ability to monitor gene
expression levels, large copy number variations in the genomic DNA, and even allows
for the identification of smaller polymorphisms (e.g. SNPs, indels, and tandem repeats).
The first aim of this thesis is to assess the SNP detection performance of a first-
generation P. falciparum microarray and to identify optimal probe features for
polymorphism detection to be incorporated in future designs. By adjusting specific probe
design parameters identified through this study, we can build high specificity while
improving sensitivity. The second aim is to use CGH microarrays to monitor genomic
changes that have occurred in a parasite line under chloroquine pressure. This approach
identifies significant genomic changes of various types which may have implications for
drug response and genome evolvability. The final aim is to globally characterize tandem
repeat sequences in the P. falciparum genome initially identified by CGH. This
previously unrecognized variation is ubiquitous and impacts the coding structures of
hundreds of genes, underscoring their potential role in genome evolution. General
characteristics of these sequences including their genome-wide distribution, their size
distribution, and common features in the tandem repeat flanking regions are described.
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