Gene copy number variation (CNV) is ubiquitous in eukaryotic genomes and the resultant dosage changes can play an important role in determining phenotype.
We aim to define the extent, evolutionary dynamics and functionality of CNV in the malaria parasite genome (Plasmodium falciparum). To achieve this we will use comparative genomic hybridization (cGH) which provides an efficient tool for assaying both CNV and single nucleotide polymorphism (SNP) and is particularly effective in haploid genomes. Preliminary data reveal abundant CNV (both deletions and amplifications) in the P. falciparum genome and demonstrate accurate prediction of SNPs. The project will be divided into three parts. First, we will identify all CNV and catalogue flanking SNPs in a worldwide parasite collection. The populations sampled will comprise freshly isolated single-clone infections from Thailand, Papua New Guinea, Colombia and Gambia. We will measure the size, gene content, and arrangement and population frequency of genome rearrangements.
Our second aim will be to evaluate evidence for adaptive evolution of genome regions showing CNV to highlight genome segments that could be influenced by recent evolutionary pressures such as selection by drugs. We will do this by examining patterns of linkage disequilibrium and haplotype structure in flanking SNP polymorphism, geographical variation in frequency, and by examination of numbers of independent origins of CNVs. Finally, we will conduct focused investigations of one CNV - containing the GTP cyclohydrolase locus - that is likely to be of functional importance. We will test the hypothesis that amplification of this gene compensates for reduced metabolic efficiency of enzymes further down the folate pathway carrying mutations that confer resistance to anti-folate compounds. This will be done using selection and transfection experiments in combination with assays of drug resistance, fitness, and flux through the folate pathway. Relevance of this research to public health. Variation in the number of gene copies can have a large influence on parasite biology. We propose to systematically describe DNA rearrangements in the malaria parasite genome, and evaluate the role that they play in this important pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI075145-05
Application #
8115173
Study Section
Special Emphasis Panel (ZRG1-IDM-G (02))
Program Officer
Joy, Deirdre A
Project Start
2007-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$393,850
Indirect Cost
Name
Texas Biomedical Research Institute
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Cheeseman, Ian H; Miller, Becky; Tan, John C et al. (2016) Population Structure Shapes Copy Number Variation in Malaria Parasites. Mol Biol Evol 33:603-20
Echeverry, Diego F; Nair, Shalini; Osorio, Lyda et al. (2013) Long term persistence of clonal malaria parasite Plasmodium falciparum lineages in the Colombian Pacific region. BMC Genet 14:2
Cheeseman, Ian H; Miller, Becky A; Nair, Shalini et al. (2012) A major genome region underlying artemisinin resistance in malaria. Science 336:79-82
Nkhoma, Standwell C; Nair, Shalini; Cheeseman, Ian H et al. (2012) Close kinship within multiple-genotype malaria parasite infections. Proc Biol Sci 279:2589-98
Anderson, Tim; Nkhoma, Standwell; Ecker, Andrea et al. (2011) How can we identify parasite genes that underlie antimalarial drug resistance? Pharmacogenomics 12:59-85
Tan, John C; Miller, Becky A; Tan, Asako et al. (2011) An optimized microarray platform for assaying genomic variation in Plasmodium falciparum field populations. Genome Biol 12:R35
Samarakoon, Upeka; Gonzales, Joseph M; Patel, Jigar J et al. (2011) The landscape of inherited and de novo copy number variants in a Plasmodium falciparum genetic cross. BMC Genomics 12:457
Nair, Shalini; Nkhoma, Standwell; Nosten, Francois et al. (2010) Genetic changes during laboratory propagation: copy number At the reticulocyte-binding protein 1 locus of Plasmodium falciparum. Mol Biochem Parasitol 172:145-8
Tan, John C; Tan, Asako; Checkley, Lisa et al. (2010) Variable numbers of tandem repeats in Plasmodium falciparum genes. J Mol Evol 71:268-78
Nkhoma, Standwell; Nair, Shalini; Mukaka, Mavuto et al. (2009) Parasites bearing a single copy of the multi-drug resistance gene (pfmdr-1) with wild-type SNPs predominate amongst Plasmodium falciparum isolates from Malawi. Acta Trop 111:78-81

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