Multiple genetic backgrounds of the amplified plasmodium falciparum multidrug resistance (Pfrndr1) gene and selective sweep of 184F mutation in Cambodia

Sumiti Vinayak, Md Tauqeer Alam, Rithy Sem, Naman K. Shah, Augustina I. Susanti, Pharath Lim, Sinuon Muth, Jason D. Maguire, William O. Rogers, Thierry Fandeur, John W. Barnwell, Ananias A. Escalante, Chansuda Wongsrichanalai, Frederick Ariey, Steven R. Meshnick, Venkatachalam Udhayakumar

Research output: Contribution to journalArticle

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Abstract

Background. The emergence of artesunate-mefloquine (AS+MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 because of the spread of adaptive mutation and/or multiple copies of this gene in the P falciparum population in Cambodia. Methods. We characterized 13 microsatellite loci flanking (±99 kb) pfmdr1 in 93 single-clone P falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 gene. Results. Genetic analysis revealed no difference in the mean ( ± standard deviation) expected heterozygosity (He) at loci around single (0.75 ± 0.03) and multiple (0.76 ± 0.04) copies of pfmdr1. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28% in mean He (±SD) around mutant allele (0.56 ± 0.05), compared with wild-type allele (0.84 ± 0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele. Conclusion. The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.

Original languageEnglish (US)
Pages (from-to)1551-1560
Number of pages10
JournalJournal of Infectious Diseases
Volume201
Issue number10
DOIs
StatePublished - May 15 2010

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Cambodia
MDR Genes
Plasmodium falciparum
Alleles
Mutation
Genes
Mefloquine
Gene Amplification
Linkage Disequilibrium
Thailand
Microsatellite Repeats
Haplotypes
Population
Malaria
Genetic Background
Clone Cells
Infection

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy
  • Medicine(all)

Cite this

Multiple genetic backgrounds of the amplified plasmodium falciparum multidrug resistance (Pfrndr1) gene and selective sweep of 184F mutation in Cambodia. / Vinayak, Sumiti; Alam, Md Tauqeer; Sem, Rithy; Shah, Naman K.; Susanti, Augustina I.; Lim, Pharath; Muth, Sinuon; Maguire, Jason D.; Rogers, William O.; Fandeur, Thierry; Barnwell, John W.; Escalante, Ananias A.; Wongsrichanalai, Chansuda; Ariey, Frederick; Meshnick, Steven R.; Udhayakumar, Venkatachalam.

In: Journal of Infectious Diseases, Vol. 201, No. 10, 15.05.2010, p. 1551-1560.

Research output: Contribution to journalArticle

Vinayak, S, Alam, MT, Sem, R, Shah, NK, Susanti, AI, Lim, P, Muth, S, Maguire, JD, Rogers, WO, Fandeur, T, Barnwell, JW, Escalante, AA, Wongsrichanalai, C, Ariey, F, Meshnick, SR & Udhayakumar, V 2010, 'Multiple genetic backgrounds of the amplified plasmodium falciparum multidrug resistance (Pfrndr1) gene and selective sweep of 184F mutation in Cambodia', Journal of Infectious Diseases, vol. 201, no. 10, pp. 1551-1560. https://doi.org/10.1086/651949
Vinayak, Sumiti ; Alam, Md Tauqeer ; Sem, Rithy ; Shah, Naman K. ; Susanti, Augustina I. ; Lim, Pharath ; Muth, Sinuon ; Maguire, Jason D. ; Rogers, William O. ; Fandeur, Thierry ; Barnwell, John W. ; Escalante, Ananias A. ; Wongsrichanalai, Chansuda ; Ariey, Frederick ; Meshnick, Steven R. ; Udhayakumar, Venkatachalam. / Multiple genetic backgrounds of the amplified plasmodium falciparum multidrug resistance (Pfrndr1) gene and selective sweep of 184F mutation in Cambodia. In: Journal of Infectious Diseases. 2010 ; Vol. 201, No. 10. pp. 1551-1560.
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abstract = "Background. The emergence of artesunate-mefloquine (AS+MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 because of the spread of adaptive mutation and/or multiple copies of this gene in the P falciparum population in Cambodia. Methods. We characterized 13 microsatellite loci flanking (±99 kb) pfmdr1 in 93 single-clone P falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 gene. Results. Genetic analysis revealed no difference in the mean ( ± standard deviation) expected heterozygosity (He) at loci around single (0.75 ± 0.03) and multiple (0.76 ± 0.04) copies of pfmdr1. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28{\%} in mean He (±SD) around mutant allele (0.56 ± 0.05), compared with wild-type allele (0.84 ± 0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele. Conclusion. The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.",
author = "Sumiti Vinayak and Alam, {Md Tauqeer} and Rithy Sem and Shah, {Naman K.} and Susanti, {Augustina I.} and Pharath Lim and Sinuon Muth and Maguire, {Jason D.} and Rogers, {William O.} and Thierry Fandeur and Barnwell, {John W.} and Escalante, {Ananias A.} and Chansuda Wongsrichanalai and Frederick Ariey and Meshnick, {Steven R.} and Venkatachalam Udhayakumar",
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T1 - Multiple genetic backgrounds of the amplified plasmodium falciparum multidrug resistance (Pfrndr1) gene and selective sweep of 184F mutation in Cambodia

AU - Vinayak, Sumiti

AU - Alam, Md Tauqeer

AU - Sem, Rithy

AU - Shah, Naman K.

AU - Susanti, Augustina I.

AU - Lim, Pharath

AU - Muth, Sinuon

AU - Maguire, Jason D.

AU - Rogers, William O.

AU - Fandeur, Thierry

AU - Barnwell, John W.

AU - Escalante, Ananias A.

AU - Wongsrichanalai, Chansuda

AU - Ariey, Frederick

AU - Meshnick, Steven R.

AU - Udhayakumar, Venkatachalam

PY - 2010/5/15

Y1 - 2010/5/15

N2 - Background. The emergence of artesunate-mefloquine (AS+MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 because of the spread of adaptive mutation and/or multiple copies of this gene in the P falciparum population in Cambodia. Methods. We characterized 13 microsatellite loci flanking (±99 kb) pfmdr1 in 93 single-clone P falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 gene. Results. Genetic analysis revealed no difference in the mean ( ± standard deviation) expected heterozygosity (He) at loci around single (0.75 ± 0.03) and multiple (0.76 ± 0.04) copies of pfmdr1. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28% in mean He (±SD) around mutant allele (0.56 ± 0.05), compared with wild-type allele (0.84 ± 0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele. Conclusion. The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.

AB - Background. The emergence of artesunate-mefloquine (AS+MQ)-resistant Plasmodium falciparum in the Thailand-Cambodia region is a major concern for malaria control. Studies indicate that copy number increase and key alleles in the pfmdr1 gene are associated with AS+MQ resistance. In the present study, we investigated evidence for a selective sweep around pfmdr1 because of the spread of adaptive mutation and/or multiple copies of this gene in the P falciparum population in Cambodia. Methods. We characterized 13 microsatellite loci flanking (±99 kb) pfmdr1 in 93 single-clone P falciparum infections, of which 31 had multiple copies and 62 had a single copy of the pfmdr1 gene. Results. Genetic analysis revealed no difference in the mean ( ± standard deviation) expected heterozygosity (He) at loci around single (0.75 ± 0.03) and multiple (0.76 ± 0.04) copies of pfmdr1. Evidence of genetic hitchhiking with the selective sweep of certain haplotypes was seen around mutant (184F) pfmdr1 allele, irrespective of the copy number. There was an overall reduction of 28% in mean He (±SD) around mutant allele (0.56 ± 0.05), compared with wild-type allele (0.84 ± 0.02). Significant linkage disequilibrium was also observed between the loci flanking mutant pfmdr1 allele. Conclusion. The 184F mutant allele is under selection, whereas amplification of pfmdr1 gene in this population occurs on multiple genetic backgrounds.

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