- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- High degree of monomorphism in the 5′ upstream region of pfmdr1.
- Identification of a polymorphic hotspot in the 5′-UTR of pfmdr1.
- Lack of a reduction of the frequency of polymorphism by TA skew.
- Higher frequency of SNPs in chloroquine-resistant strains than in chloroquine-sensitive strains.
- Dominance of the T→C 328 SNP in a population of Senegalese field isolates.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1
Rich SM, Licht MC, Hudson RR, Ayala FJ, 1998. Malaria’s Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum. Proc Natl Acad Sci USA 95 :4425–4430.
-
2
Volkman SK, Barry AE, Lyons EJ, Nielsen KM, Thomas SM, Choi M, Thakore SS, Day KP, Wirth DF, Hartl DL, 2001. Recent origin of Plasmodium falciparum from a single progenitor. Science 293 :482–484.
-
3
Volkman SK, Hartl DL, Wirth DF, Nielsen KM, Choi M, Batalov S, Zhou Y, Plouffe D, Le Roch KG, Abagyan R, Winzeler EA, 2002. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science 298 :216–218.
-
4
Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ, 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418 :320–323.
-
5
Rich SM, Ayala FJ, 2000. Population structure and recent evolution of Plasmodium falciparum. Proc Natl Acad Sci USA 97 :6994–7001.
-
6
Hughes AL, Verra F, 2002. Extensive polymorphism and ancient origin of Plasmodium falciparum. Trends Parasitol 18 :348–351.
-
7
Joy DA, Feng X, Mu J, Furuya T, Chotivanich K, Krettli AU, Ho M, Wang A, White NJ, Suh E, Beerli P, Su XZ, 2003. Early origin and recent expansion of Plasmodium falciparum. Science 300 :318–321.
-
8
Jongwutiwes S, Putaporntip C, Friedman R, Hughes AL, 2002. The extent of nucleotide polymorphism is highly variable across a 3-kb region on Plasmodium falciparum chromosome 2. Mol Biol Evol 19 :1585–1590.
-
9
Gupta S, Anderson RM, 1999. Population structure of pathogens: the role of immune selection. Parasitol Today 15 :497–501.
-
10
Anderson TJ, Haubold B, Williams JT, Estrada-Franco JG, Richardson L, Mollinedo R, Bockarie M, Mokili J, Mharakurwa S, French N, Whitworth J, Velez ID, Brockman AH, Nosten F, Ferreira MU, Day KP, 2000. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol Biol Evol 17 :1467–1482.
-
11
Conway DJ, Roper C, Oduola AM, Arnot DE, Kremsner PG, Grobusch MP, Curtis CF, Greenwood BM, 1999. High recombination rate in natural populations of Plasmodium falciparum. Proc Natl Acad Sci USA 96 :4506–4511.
-
12
Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345 :255–258.
-
13
Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403 :906–909.
-
14
Price RN, Cassar C, Brockman A, Duraisingh M, van Vugt M, White NJ, Nosten F, Krishna S, 1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob Agents Chemother 43 :2943–2949.
-
15
Lopes D, Rungsihirunrat K, Nogueira F, Seugorn A, Gil JP, Do Rosario VE, Cravo P, 2002. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand. Malar J 1 :12.
-
16
Mockenhaupt FP, Eggelte TA, Till H, Bienzle U, 2001. Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana. Trop Med Int Health 6 :749–755.
-
17
Babiker HA, Pringle SJ, Abdel-Muhsin A, Mackinnon M, Hunt P, Walliker D, 2001. High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. J Infect Dis 183 :1535–1538.
-
18
Duraisingh MT, von Seidlein LV, Jepson A, Jones P, Sambou I, Pinder M, Warhurst DC, 2000. Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum. Parasitology 121 :1–7.
-
19
Adagut IS, Warhurst DC, 2001. Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in northern Nigeria. Parasitology 123 :219–224.
-
20
Thomas SM, Ndir O, Dieng T, Mboup S, Wypij D, Maguire JH, Wirth DF, 2002. In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal. Am J Trop Med Hyg 66 :474–480.
-
21
Daily JPRC, Thomas SM, Ndir O, Dieng T, Mboup S, Wirth DF, 2003. Prevalence of Plasmodium falciparum pfcrt polymorphisms and in vitro chloroquine sensitivity in Senegal. Parasitology 126 :401–405.
-
22
Sidhu AB, Verdier-Pinard D, Fidock DA, 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 :210–213.
-
23
Plasmodium Genome Database Collaborative, 2001. PlasmoDB: an integrative database of the Plasmodium falciparum genome. Tools for accessing and analyzing finished and unfinished sequence data. The Plasmodium Genome Database Collaborative. Nucleic Acids Res 29 :66–69.
-
24
Myrick A, Munasinghe A, Patankar S, Wirth DF, 2003. Mapping of the Plasmodium falciparum multidrug resistance gene 5′-upstream region, and evidence of induction of transcript levels by antimalarial drugs in chloroquine sensitive parasites. Mol Microbiol 49 :671–683.
-
25
Rondan Duenas JC, Panzetta-Dutari GM, Gardenal CN, 1999. Specific requirements for PCR amplification of long mitochondrial A+T-rich DNA. Biotechniques 27 :258–260.
-
26
Moreno A, Brasseur P, Cuzin-Ouattara N, Blanc C, Druilhe P, 2001. Evaluation under field conditions of the colourimetric DELI-microtest for the assessment of Plasmodium falciparum drug resistance. Trans R Soc Trop Med Hyg 95 :100–103.
-
27
Druilhe P, Moreno A, Blanc C, Brasseur PH, Jacquier P, 2001. A colorimetric in vitro drug sensitivity assay for Plasmodium falciparum based on a highly sensitive double-site lactate dehydrogenase antigen-capture enzyme-linked immunosorbent assay. Am J Trop Med Hyg 64 :233–241.
-
28
Lobry JR, 1996. Asymmetric substitution patterns in the two DNA strands of bacteria. Mol Biol Evol 13 :660–665.
-
29
Rozas J, Rozas R, 1999. DnaSP version 3: An integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics 15 :174–175.
-
30
Hartl DL, 2000. A Primer of Population Genetics. Sunderland, MA: Sinauer Associates.
-
31
Levinson G, Gutman GA, 1987. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol 4 :203–221.
-
32
Mu J, Duan J, Makova KD, Joy DA, Huynh CQ, Branch OH, Li WH, Su XZ, 2002. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418 :323–326.
-
33
Rathod PK, McErlean T, Lee PC, 1997. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 94 :9389–9393.
| Past two years | Past Year | Past 30 Days | |
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| Abstract Views | 112 | 66 | 4 |
| Full Text Views | 240 | 6 | 0 |
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ANALYSIS OF THE GENETIC DIVERSITY OF THE PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE GENE 5′ UPSTREAM REGION
ALISSA MYRICK
ALISSA MYRICK
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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OUSMANE SARR
OUSMANE SARR
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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THERESE DIENG
THERESE DIENG
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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OMAR NDIR
OMAR NDIR
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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SOULEYMANE MBOUP
SOULEYMANE MBOUP
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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DYANN F. WIRTH
DYANN F. WIRTH
Department of Medicine, San Francisco General Hospital, University of California at San Francisco, San Francisco, California; Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal; Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts
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Recent findings indicating a low level of polymorphism in the Plasmodium falciparum genome have led to the hypothesis that existent polymorphisms are likely to have functional significance. We tested this hypothesis by developing a map of the polymorphism in the P. falciparum multidrug resistance 1 (pfmdr1) gene 5′ upstream region and assaying its correlation with drug resistance in a sample of field isolates from Dakar, Senegal. A comparison of six geographically diverse laboratory strains showed that the 1.94-kb 5′-untranslated region is highly monomorphic, with a total of four unique single nucleotide polymorphisms (SNPs) being identified. All of the mutations were localized to a 462-basepair region proximal to the transcription start point. Analysis of this region in field isolates shows the prevalence of one SNP throughout the entire population of parasites, irrespective of drug resistance status. The SNP frequency of the pfmdr1 upstream region is lower than that found in the noncoding region of other genes.
Author Notes
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- High degree of monomorphism in the 5′ upstream region of pfmdr1.
- Identification of a polymorphic hotspot in the 5′-UTR of pfmdr1.
- Lack of a reduction of the frequency of polymorphism by TA skew.
- Higher frequency of SNPs in chloroquine-resistant strains than in chloroquine-sensitive strains.
- Dominance of the T→C 328 SNP in a population of Senegalese field isolates.
- DISCUSSION
ProCite
RefWorks
Reference Manager
BibTeX
Zotero
EndNote
-
1
Rich SM, Licht MC, Hudson RR, Ayala FJ, 1998. Malaria’s Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum. Proc Natl Acad Sci USA 95 :4425–4430.
-
2
Volkman SK, Barry AE, Lyons EJ, Nielsen KM, Thomas SM, Choi M, Thakore SS, Day KP, Wirth DF, Hartl DL, 2001. Recent origin of Plasmodium falciparum from a single progenitor. Science 293 :482–484.
-
3
Volkman SK, Hartl DL, Wirth DF, Nielsen KM, Choi M, Batalov S, Zhou Y, Plouffe D, Le Roch KG, Abagyan R, Winzeler EA, 2002. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science 298 :216–218.
-
4
Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ, 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418 :320–323.
-
5
Rich SM, Ayala FJ, 2000. Population structure and recent evolution of Plasmodium falciparum. Proc Natl Acad Sci USA 97 :6994–7001.
-
6
Hughes AL, Verra F, 2002. Extensive polymorphism and ancient origin of Plasmodium falciparum. Trends Parasitol 18 :348–351.
-
7
Joy DA, Feng X, Mu J, Furuya T, Chotivanich K, Krettli AU, Ho M, Wang A, White NJ, Suh E, Beerli P, Su XZ, 2003. Early origin and recent expansion of Plasmodium falciparum. Science 300 :318–321.
-
8
Jongwutiwes S, Putaporntip C, Friedman R, Hughes AL, 2002. The extent of nucleotide polymorphism is highly variable across a 3-kb region on Plasmodium falciparum chromosome 2. Mol Biol Evol 19 :1585–1590.
-
9
Gupta S, Anderson RM, 1999. Population structure of pathogens: the role of immune selection. Parasitol Today 15 :497–501.
-
10
Anderson TJ, Haubold B, Williams JT, Estrada-Franco JG, Richardson L, Mollinedo R, Bockarie M, Mokili J, Mharakurwa S, French N, Whitworth J, Velez ID, Brockman AH, Nosten F, Ferreira MU, Day KP, 2000. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol Biol Evol 17 :1467–1482.
-
11
Conway DJ, Roper C, Oduola AM, Arnot DE, Kremsner PG, Grobusch MP, Curtis CF, Greenwood BM, 1999. High recombination rate in natural populations of Plasmodium falciparum. Proc Natl Acad Sci USA 96 :4506–4511.
-
12
Foote SJ, Kyle DE, Martin RK, Oduola AM, Forsyth K, Kemp DJ, Cowman AF, 1990. Several alleles of the multidrug-resistance gene are closely linked to chloroquine resistance in Plasmodium falciparum. Nature 345 :255–258.
-
13
Reed MB, Saliba KJ, Caruana SR, Kirk K, Cowman AF, 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403 :906–909.
-
14
Price RN, Cassar C, Brockman A, Duraisingh M, van Vugt M, White NJ, Nosten F, Krishna S, 1999. The pfmdr1 gene is associated with a multidrug-resistant phenotype in Plasmodium falciparum from the western border of Thailand. Antimicrob Agents Chemother 43 :2943–2949.
-
15
Lopes D, Rungsihirunrat K, Nogueira F, Seugorn A, Gil JP, Do Rosario VE, Cravo P, 2002. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand. Malar J 1 :12.
-
16
Mockenhaupt FP, Eggelte TA, Till H, Bienzle U, 2001. Plasmodium falciparum pfcrt and pfmdr1 polymorphisms are associated with the pfdhfr N108 pyrimethamine-resistance mutation in isolates from Ghana. Trop Med Int Health 6 :749–755.
-
17
Babiker HA, Pringle SJ, Abdel-Muhsin A, Mackinnon M, Hunt P, Walliker D, 2001. High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance gene pfmdr1. J Infect Dis 183 :1535–1538.
-
18
Duraisingh MT, von Seidlein LV, Jepson A, Jones P, Sambou I, Pinder M, Warhurst DC, 2000. Linkage disequilibrium between two chromosomally distinct loci associated with increased resistance to chloroquine in Plasmodium falciparum. Parasitology 121 :1–7.
-
19
Adagut IS, Warhurst DC, 2001. Plasmodium falciparum: linkage disequilibrium between loci in chromosomes 7 and 5 and chloroquine selective pressure in northern Nigeria. Parasitology 123 :219–224.
-
20
Thomas SM, Ndir O, Dieng T, Mboup S, Wypij D, Maguire JH, Wirth DF, 2002. In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal. Am J Trop Med Hyg 66 :474–480.
-
21
Daily JPRC, Thomas SM, Ndir O, Dieng T, Mboup S, Wirth DF, 2003. Prevalence of Plasmodium falciparum pfcrt polymorphisms and in vitro chloroquine sensitivity in Senegal. Parasitology 126 :401–405.
-
22
Sidhu AB, Verdier-Pinard D, Fidock DA, 2002. Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 :210–213.
-
23
Plasmodium Genome Database Collaborative, 2001. PlasmoDB: an integrative database of the Plasmodium falciparum genome. Tools for accessing and analyzing finished and unfinished sequence data. The Plasmodium Genome Database Collaborative. Nucleic Acids Res 29 :66–69.
-
24
Myrick A, Munasinghe A, Patankar S, Wirth DF, 2003. Mapping of the Plasmodium falciparum multidrug resistance gene 5′-upstream region, and evidence of induction of transcript levels by antimalarial drugs in chloroquine sensitive parasites. Mol Microbiol 49 :671–683.
-
25
Rondan Duenas JC, Panzetta-Dutari GM, Gardenal CN, 1999. Specific requirements for PCR amplification of long mitochondrial A+T-rich DNA. Biotechniques 27 :258–260.
-
26
Moreno A, Brasseur P, Cuzin-Ouattara N, Blanc C, Druilhe P, 2001. Evaluation under field conditions of the colourimetric DELI-microtest for the assessment of Plasmodium falciparum drug resistance. Trans R Soc Trop Med Hyg 95 :100–103.
-
27
Druilhe P, Moreno A, Blanc C, Brasseur PH, Jacquier P, 2001. A colorimetric in vitro drug sensitivity assay for Plasmodium falciparum based on a highly sensitive double-site lactate dehydrogenase antigen-capture enzyme-linked immunosorbent assay. Am J Trop Med Hyg 64 :233–241.
-
28
Lobry JR, 1996. Asymmetric substitution patterns in the two DNA strands of bacteria. Mol Biol Evol 13 :660–665.
-
29
Rozas J, Rozas R, 1999. DnaSP version 3: An integrated program for molecular population genetics and molecular evolution analysis. Bioinformatics 15 :174–175.
-
30
Hartl DL, 2000. A Primer of Population Genetics. Sunderland, MA: Sinauer Associates.
-
31
Levinson G, Gutman GA, 1987. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol Biol Evol 4 :203–221.
-
32
Mu J, Duan J, Makova KD, Joy DA, Huynh CQ, Branch OH, Li WH, Su XZ, 2002. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418 :323–326.
-
33
Rathod PK, McErlean T, Lee PC, 1997. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc Natl Acad Sci USA 94 :9389–9393.
| Past two years | Past Year | Past 30 Days | |
|---|---|---|---|
| Abstract Views | 112 | 66 | 4 |
| Full Text Views | 240 | 6 | 0 |
| PDF Downloads | 48 | 9 | 0 |