Intercontinental Spread of Pyrimethamine-Resistant Malaria

Roper, Cally; Pearce, R. P.; Nair, Shalini; Sharp, Brian; Nosten, François; Anderson, Tim

doi:10.1126/science.1098876

Cited by 456 publications

(416 citation statements)

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“…There is evidence of recent selective sweeps across specific regions of the genome, presumably as a consequence of recent drug pressure (Wootton et al, 2002;Nair et al, 2003;Roper, 2003;Roper, 2004). Older selective sweeps as a consequence of natural selection may have occurred across the genome, but identification of these regions might require a genome-wide haplotype map and analysis of linkage disequilibrium.…”

Section: Discussionmentioning

confidence: 99%

“…Regions of the genome that have undergone recent selective sweeps include regions of chromosome 7 surrounding the pfcrt locus (Wootton et al, 2002) and regions of chromosome 4 surrounding the dhfr (Nair et al, 2003;Roper et al, 2003) and dhps (Roper et al, 2004) loci. These selective sweeps are recent in the evolutionary history of P. falciparum, presumably because they are a consequence of recently applied drug pressure.…”

Section: Introductionmentioning

confidence: 99%

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Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

Volkman

Lozovsky

Barry

et al. 2007

Gene

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The density and distribution of single-nucleotide polymorphisms (SNPs) across the genome has important implications for linkage disequilibrium mapping and association studies, and the level of simple-sequence microsatellite polymorphisms has important implications for the use of oligonucleotide hybridization methods to genotype SNPs. To assess the density of these types of polymorphisms in P. falciparum, we sampled introns and noncoding DNA upstream and downstream of coding regions among a variety of geographically diverse parasites. Across 36,229 base pairs of noncoding sequence representing 41 genetic loci, a total of 307 polymorphisms including 248 polymorphic microsatellites and 39 SNPs were identified. We found a significant excess of microsatellite polymorphisms having a repeat unit length of one or two, compared to those with longer repeat lengths, as well as a nonrandom distribution of SNP polymorphisms. Almost half of the SNPs localized to only three of the 41 genetic loci sampled. Furthermore, we find significant differences in the frequency of polymorphisms across the two chromosomes (2 and 3) examined most extensively, with an excess of SNPs and a surplus of polymorphic microsatellites on chromosome 3 as compared to chromosome 2 (P = 0.0001). Furthermore, at some individual genetic loci we also find a nonrandom distribution of polymorphisms between coding and flanking noncoding sequences, where completely monomorphic regions may flank highly polymorphic genes. These data, combined with our previous findings of nonrandom distribution of SNPs across chromosome 2, suggest that the Plasmodium falciparum genome may be a mosaic with regard to genetic diversity, containing chromosomal regions that are highly polymorphic interspersed with regions that are much less polymorphic.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

Volkman

Lozovsky

Barry

et al. 2007

Gene

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“…They detected several selective sweeps associated with CQ resistance, including the previously described region on chromosome 7 containing pfcrt, as well as loci on chromosomes 5 (harboring the multidrug resistance gene homolog pfmdr1) and 11. Focusing on pyrimethamine resistant clones, they were able to detect two candidate selective sweeps on chromosomes 13 and 14, which were of particular interest because they demonstrated a stronger signal than the previously identified sweep at the dhfr locus on chromosome 4 [9,13,14].…”

Section: Genomic Studies Using Polymorphisms To Identify Resistance Locimentioning

confidence: 95%

“…Roper et al [9] analyzed microsatellites surrounding alleles of the dihydrofolate reductase (dhfr) gene that confer resistance to pyrimethamine. They concluded that the most resistant form of dhfr commonly found in Africa, characterized by three point mutations, was associated with a set of related haplotypes that originated in Southeast Asia (Figure 1).…”

Section: Genomic Studies Using Polymorphisms To Identify Resistance Locimentioning

confidence: 99%

Advances in understanding the genetic basis of antimalarial drug resistance

Ekland

Fidock

2007

Current Opinion in Microbiology

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SummaryThe acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine-pyrimethamine. Genetic approaches have also been designed to predict determinants of in vivo resistance to new antimalarials such as the artemisinins. Transfection methodologies have defined the role of determinants including pfcrt, pfmdr1 and dhfr. This knowledge can be leveraged to develop more efficient methods of surveillance and treatment.

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“…[50][51][52][53][54][55] In the past, drug-use patterns in Africa readily fostered partly resistant parasites, but highgrade resistance originated from Asia. 56,57 Drug-use patterns in Africa have changed substantially in the past decade and much investment has been made to improve availability of drugs and provision of chemoprevention for vulnerable groups. De-novo emergence of resistance is most likely to occur in areas of low transmission, low immunity, and high parasite load in infected individuals, where a high proportion of infected people have symptoms and seek treatment.…”

Section: Parasite Resistancementioning

confidence: 99%

Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems

Talisuna

Karema

Ogutu

et al. 2012

The Lancet Infectious Diseases

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Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and has been detected in western Thailand. The situation is ominously reminiscent of the emergence of resistance to chloroquine and to sulfadoxine-pyrimethamine several decades ago. Artemisinin resistance is a major threat to global public health, with the most severe potential effects in subSaharan Africa, where the disease burden is highest and systems for monitoring and containment of resistance are inadequate. The mechanisms that underlie artemisinin resistance are not fully understood. The main phenotypic trait associated with resistance is a substantial delay in parasite clearance, so far reported in southeast Asia but not in Africa. One of the pillars of the WHO global plan for artemisinin resistance containment is to increase monitoring and surveillance. In this Personal View, we propose strategies that should be adopted by malaria-endemic countries in Africa: resource mobilisation to reactivate regional surveillance networks, establishment of baseline parasite clearance profiles to serve as benchmarks to track emerging artemisinin resistance, improved data sharing to allow pooled analyses to identify rare events, modelling of risk factors for drug resistance, and development and validation of new approaches to monitor resistance.

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Intercontinental Spread of Pyrimethamine-Resistant Malaria

Cited by 456 publications

References 10 publications

Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

Advances in understanding the genetic basis of antimalarial drug resistance

Mitigating the threat of artemisinin resistance in Africa: improvement of drug-resistance surveillance and response systems

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