Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax
Background Chloroquine combined with primaquine has been the ecommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug resi...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Journal Article |
| Language: | Inglés |
| Published: |
Public Library of Science
2015
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10568/69468 |
| _version_ | 1855522764144771072 |
|---|---|
| author | Schousboe, M.L. Ranjitkar, S. Rajakaruna, R.S. Amerasinghe, Priyanie H. Morales, Francisco José Pearce, R. Ord, R. Leslie, T. Rowland, M. Gadalla, N.B. Konradsen, Flemming Bygbjerg, C. Roper, C. Alifrangis, M. |
| author_browse | Alifrangis, M. Amerasinghe, Priyanie H. Bygbjerg, C. Gadalla, N.B. Konradsen, Flemming Leslie, T. Morales, Francisco José Ord, R. Pearce, R. Rajakaruna, R.S. Ranjitkar, S. Roper, C. Rowland, M. Schousboe, M.L. |
| author_facet | Schousboe, M.L. Ranjitkar, S. Rajakaruna, R.S. Amerasinghe, Priyanie H. Morales, Francisco José Pearce, R. Ord, R. Leslie, T. Rowland, M. Gadalla, N.B. Konradsen, Flemming Bygbjerg, C. Roper, C. Alifrangis, M. |
| author_sort | Schousboe, M.L. |
| collection | Repository of Agricultural Research Outputs (CGSpace) |
| description | Background
Chloroquine combined with primaquine has been the ecommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored.
Objective
In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS) loci flanking the Pvmdr1 gene.
Methods
We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, Sao Tome and Ecuador. We measured and diversity in four microsatellite (MS) markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles.
Results
SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5), 13.3% (n =28) of the samples were single mutant MYF, 63.0% of samples (n = 133) were double mutant MYL, and 21.3%(n = 45) were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD) between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He), was seen in the complete sample set (He = 0.99), while He estimates for individual loci ranged from 0.00–0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic sites which could indicate directional selection through local drug pressure.
Conclusions
Our observations suggest that Pvmdr1 mutations emerged independently on multiple occasions even within the same population. In Sri Lanka population analysis at multiple sites showed evidence of local selection and geographical dispersal of Pvmdr1 mutations between sites. |
| format | Journal Article |
| id | CGSpace69468 |
| institution | CGIAR Consortium |
| language | Inglés |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | Public Library of Science |
| publisherStr | Public Library of Science |
| record_format | dspace |
| spelling | CGSpace694682025-06-17T08:23:35Z Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax Schousboe, M.L. Ranjitkar, S. Rajakaruna, R.S. Amerasinghe, Priyanie H. Morales, Francisco José Pearce, R. Ord, R. Leslie, T. Rowland, M. Gadalla, N.B. Konradsen, Flemming Bygbjerg, C. Roper, C. Alifrangis, M. medical sciences mutation malaria drugs codons genes dna microsatellites Background Chloroquine combined with primaquine has been the ecommended antimalarial treatment of Plasmodium vivax malaria infections for six decades but the efficacy of this treatment regimen is threatened by chloroquine resistance (CQR). Single nucleotide polymorphisms (SNPs) in the multidrug resistance gene, Pvmdr1 are putative determinants of CQR but the extent of their emergence at population level remains to be explored. Objective In this study we describe the prevalence of SNPs in the Pvmdr1 among samples collected in seven P. vivax endemic countries and we looked for molecular evidence of drug selection by characterising polymorphism at microsatellite (MS) loci flanking the Pvmdr1 gene. Methods We examined the prevalence of SNPs in the Pvmdr1 gene among 267 samples collected from Pakistan, Afghanistan, Sri Lanka, Nepal, Sudan, Sao Tome and Ecuador. We measured and diversity in four microsatellite (MS) markers flanking the Pvmdr1 gene to look evidence of selection on mutant alleles. Results SNP polymorphism in the Pvmdr1 gene was largely confined to codons T958M, Y976F and F1076L. Only 2.4% of samples were wildtype at all three codons (TYF, n = 5), 13.3% (n =28) of the samples were single mutant MYF, 63.0% of samples (n = 133) were double mutant MYL, and 21.3%(n = 45) were triple mutant MFL. Clear geographic differences in the prevalence of these Pvmdr mutation combinations were observed. Significant linkage disequilibrium (LD) between Pvmdr1 and MS alleles was found in populations sampled in Ecuador, Nepal and Sri Lanka, while significant LD between Pvmdr1 and the combined 4 MS locus haplotype was only seen in Ecuador and Sri Lanka. When combining the 5 loci, high level diversity, measured as expected heterozygosity (He), was seen in the complete sample set (He = 0.99), while He estimates for individual loci ranged from 0.00–0.93. Although Pvmdr1 haplotypes were not consistently associated with specific flanking MS alleles, there was significant differentiation between geographic sites which could indicate directional selection through local drug pressure. Conclusions Our observations suggest that Pvmdr1 mutations emerged independently on multiple occasions even within the same population. In Sri Lanka population analysis at multiple sites showed evidence of local selection and geographical dispersal of Pvmdr1 mutations between sites. 2015 2016-01-06T04:17:58Z 2016-01-06T04:17:58Z Journal Article https://hdl.handle.net/10568/69468 en Open Access Public Library of Science Schousboe, M. L.; Ranjitkar, S.; Rajakaruna, R. S.; Amerasinghe, Priyanie H.; Morales, F.; Pearce, R.; Ord, R.; Leslie, T.; Rowland, M.; Gadalla, N. B.; Konradsen, F.; Bygbjerg, C.; Roper, C.; Alifrangis, M. 2015. Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax. PLoS Neglected Tropical Diseases, 9(11):1-17. doi: https://doi.org/10.1371/journal.pntd.0004196 |
| spellingShingle | medical sciences mutation malaria drugs codons genes dna microsatellites Schousboe, M.L. Ranjitkar, S. Rajakaruna, R.S. Amerasinghe, Priyanie H. Morales, Francisco José Pearce, R. Ord, R. Leslie, T. Rowland, M. Gadalla, N.B. Konradsen, Flemming Bygbjerg, C. Roper, C. Alifrangis, M. Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title | Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title_full | Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title_fullStr | Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title_full_unstemmed | Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title_short | Multiple origins of mutations in the mdr1 gene—a putative marker of chloroquine resistance in P. vivax |
| title_sort | multiple origins of mutations in the mdr1 gene a putative marker of chloroquine resistance in p vivax |
| topic | medical sciences mutation malaria drugs codons genes dna microsatellites |
| url | https://hdl.handle.net/10568/69468 |
| work_keys_str_mv | AT schousboeml multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT ranjitkars multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT rajakarunars multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT amerasinghepriyanieh multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT moralesfranciscojose multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT pearcer multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT ordr multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT lesliet multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT rowlandm multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT gadallanb multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT konradsenflemming multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT bygbjergc multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT roperc multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax AT alifrangism multipleoriginsofmutationsinthemdr1geneaputativemarkerofchloroquineresistanceinpvivax |