Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

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Orjuela-Sanchez, Pamela ^[1] ; Karunaweera, Nadira D. ^[2] ; da Silva-Nunes, Monica ^{[1, 3]} ; da Silva, Natal S. ^[1] ; Scopel, Kezia K. G. ^{[1, 4]} ; Goncalves, Raquel M. ^[1] ; Amaratunga, Chanaki ^[5] ; Sa, Juliana M. ^[5] ; Socheat, Duong ^[6] ; Fairhust, Rick M. ^[5] ; Gunawardena, Sharmini ^[2] ; Thavakodirasah, Thuraisamy ^[7] ; Galapaththy, Gawrie L. N. ^[7] ; Abeysinghe, Rabindra ^[7] ; Kawamoto, Fumihiko ^[8] ; Wirth, Dyann F. ^[9] ; Ferreira, Marcelo U. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, BR-05508900 Sao Paulo - Brazil

^[2] Univ Colombo, Fac Med, Dept Parasitol, Colombo 8 - Sri Lanka

^[3] Univ Fed Acre, Ctr Hlth Sci, BR-69915900 Rio Branco, Acre - Brazil

^[4] Univ Fed Juiz de Fora, Inst Biol Sci, BR-36036330 Juiz De Fora, MG - Brazil

^[5] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 - USA

^[6] Natl Malaria Ctr, Phnom Penh 1 - Cambodia

^[7] Minist Hlth, Colombo 10 - Sri Lanka

^[8] Oita Univ, Inst Sci Res, Dept Social & Environm Med, Oita 8795593 - Japan

^[9] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 - USA

• Tipo de documento: Artigo Científico
• Fonte: BMC GENETICS; v. 11, JUL 13 2010.
• Citações Web of Science: 38

Resumo

Background: 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. Results: 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 similar to 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. Conclusion: 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. (AU)

• Processo FAPESP: 05/51988-0 - Epidemiologia da malaria: fatores de risco, distribuicao espaco-temporal e resposta ao tratamento em uma coorte rural amazonica.
• Beneficiário: Marcelo Urbano Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/51199-0 - Diversidade genetica, estrutura populacional e dinamica de transmissao de plasmodium vivax na amazonia rural brasileira.
• Beneficiário: Marcelo Urbano Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular