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

Orjuela-Sánchez P, Karunaweera ND, da Silva-Nunes M, da Silva NS, Scopel KK, Gonçalves RM, Amaratunga C, Sá JM, Socheat D, Fairhust RM, Gunawardena S, Thavakodirasah T, Galapaththy GL, Abeysinghe R, Kawamoto F, Wirth DF, Ferreira MU - BMC Genet. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Brazil.

ABSTRACT

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 ~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.

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Related in: MedlinePlus

Diversity at silent and nonsynonymous SNPs (SNP π) across chromosome 8 by P. vivax population. Error bars indicate standard errors of the means, derived from bootstrapping. Significantly lower nonsynonymous SNP diversity was found in all populations but Sri Lanka (P < 0.001 by Wilcoxon test).
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Figure 1: Diversity at silent and nonsynonymous SNPs (SNP π) across chromosome 8 by P. vivax population. Error bars indicate standard errors of the means, derived from bootstrapping. Significantly lower nonsynonymous SNP diversity was found in all populations but Sri Lanka (P < 0.001 by Wilcoxon test).

Mentions: The observed ranking of country-specific numbers of segregating sites and SNP π values (Sri Lanka > Brazil > Cambodia > Vietnam) does not match the ranking of malaria endemicity at the time of sample collection (Vietnam > Cambodia > Brazil > Sri Lanka). The trend towards a negative correlation between levels of genetic diversity and malaria transmission contrasts with the pattern observed for P. falciparum, for which highest diversity is seen in high-transmission settings [8,15]. This contrast is surprising and may reflect differences in the demographic history and biology of these major human parasites. In all countries but Sri Lanka, SNP π values were significantly higher for 75 silent (synonymous or noncoding) SNPs than for 10 nonsynonymous SNPs (Figure 1), consistent with nonsynonymous SNPs being often subject to purifying selection in P. vivax populations, as previously suggested for P. falciparum [15].


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

Orjuela-Sánchez P, Karunaweera ND, da Silva-Nunes M, da Silva NS, Scopel KK, Gonçalves RM, Amaratunga C, Sá JM, Socheat D, Fairhust RM, Gunawardena S, Thavakodirasah T, Galapaththy GL, Abeysinghe R, Kawamoto F, Wirth DF, Ferreira MU - BMC Genet. (2010)

Diversity at silent and nonsynonymous SNPs (SNP π) across chromosome 8 by P. vivax population. Error bars indicate standard errors of the means, derived from bootstrapping. Significantly lower nonsynonymous SNP diversity was found in all populations but Sri Lanka (P < 0.001 by Wilcoxon test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2910014&req=5

Figure 1: Diversity at silent and nonsynonymous SNPs (SNP π) across chromosome 8 by P. vivax population. Error bars indicate standard errors of the means, derived from bootstrapping. Significantly lower nonsynonymous SNP diversity was found in all populations but Sri Lanka (P < 0.001 by Wilcoxon test).
Mentions: The observed ranking of country-specific numbers of segregating sites and SNP π values (Sri Lanka > Brazil > Cambodia > Vietnam) does not match the ranking of malaria endemicity at the time of sample collection (Vietnam > Cambodia > Brazil > Sri Lanka). The trend towards a negative correlation between levels of genetic diversity and malaria transmission contrasts with the pattern observed for P. falciparum, for which highest diversity is seen in high-transmission settings [8,15]. This contrast is surprising and may reflect differences in the demographic history and biology of these major human parasites. In all countries but Sri Lanka, SNP π values were significantly higher for 75 silent (synonymous or noncoding) SNPs than for 10 nonsynonymous SNPs (Figure 1), consistent with nonsynonymous SNPs being often subject to purifying selection in P. vivax populations, as previously suggested for P. falciparum [15].

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Brazil.

ABSTRACT

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 ~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.

Show MeSH
Related in: MedlinePlus