Diss. (sammanfattning) Uppsala : Uppsala universitet, 2009.

Duplications and deletions are a major source of genomic variation. Duplications, specifically, have a significant impact on gene genesis and dosage, and the malaria parasite P. falciparum has developed resistance to a growing number of anti-malarial drugs via gene duplication. It also contains highly duplicated families of antigenically variable allelic genes. While specific genes and families have been studied, a comprehensive analysis of duplications and deletions within the reference genome and population has not been performed. We analyzed the extent of segmental duplications (SD) in the reference genome for P. falciparum, primarily by a whole genome self alignment. We discovered that while 5% of the genome identified as SD, the distribution within the genome was partition clustered, with the vast majority localized to the subtelomeres. Within the SDs, we found an overrepresentation of genes encoding antigenically diverse proteins exposed to the extracellular membrane, specifically the var, rifin, and stevor gene families. To examine variation of duplications and deletions within the parasite populations, we designed a novel computational methodology to identify copy number variants (CNVs) from high throughput sequencing, using a read depth based approach refined with discordant read pairs. After validating the program against in vitro lab cultures, we analyzed isolates from Senegal for initial tests into clinical isolates. We then expanded our search to a global sample of 610 strains from Africa and South East Asia, identifying 68 CNV regions. Geographically, genic CNV were found on average in less than 10% of the population, indicating that CNV are rare. However, CNVs at high frequency were almost exclusively duplications associated with known drug resistant CNVs. We also identified the novel biallelic duplication of the crt gene – containing both the chloroquine resistant and sensitive allele. The synthesis of our SD and CNV analysis indicates a CNV conservative P. falciparum genome except where drug and human immune pressure select for gene duplication.