Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies
1 Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, São Paulo, Brazil
2 Department of Parasitology, Faculty of Medicine, University of Colombo, Kinsey Road, Colombo 8, Sri Lanka
3 Center of Health Sciences, Federal University of Acre, 69915-900 Rio Branco, Acre, Brazil
4 Institute of Biological Sciences, Federal University of Juiz de Fora, 36036-330 Juiz de Fora, Minas Gerais, Brazil
5 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
6 National Malaria Center, Phnom Penh 1, Cambodia
7 Anti-Malaria Campaign, Ministry of Health, Colombo 10, Sri Lanka
8 Department of Social and Environmental Medicine, Institute of Scientific Research, Oita University, Oita 879-5593 Japan
9 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
BMC Genetics 2010, 11:65 doi:10.1186/1471-2156-11-65Published: 13 July 2010
The ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite P. vivax remain little characterized.
We examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of P. vivax in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of P. vivax. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the pvmdr-1 locus, putatively associated with drug resistance.
These findings support the feasibility of genome-wide association studies in carefully selected populations of P. vivax, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.