Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

Gomes, Ana; Ravenhall, Matt; Benavente, Ernest Diez; Talman, Arthur M.; Sutherland, Colin J.; Roper, Cally; Clark, Taane G.; Campino, Susana

doi:10.1016/j.ijpddr.2017.03.001

Cited by 12 publications

(15 citation statements)

References 17 publications

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“…The results tabulated by Gomes et al [5] are different to the results of this research. In particular, Gomes et al [5] do not report the PfATP4 synonymous SNP G223G (C669A, 35% of all isolates) characteristic of the Pf strain Dd2 [14] or G223S (G667A, 8.9% of all isolates) present in African populations. It should be noted that the G667A and C669A SNPs (GGC→AGA) occuring together produce the G223R resistance mutation.…”

Section: Introductioncontrasting

confidence: 99%

“…It should be noted that the G667A and C669A SNPs (GGC→AGA) occuring together produce the G223R resistance mutation. The probable reason for the difference between Gomes et al [5] and this research appears to be different variant calling methodology. Whereas Gomes et al [5] use Delly (Rausch et al [13]) to call variants, this research does not attempt to independently discover variants, but uses the Pf3k VCF files generated by MalariaGen using GATK.…”

Section: Introductioncontrasting

confidence: 70%

“…This was done by Gomes et al [5] for a number of drug target proteins including PfATP4 using Delly software (Rausch et al [13]) to analyze Pf3k BAM files and generate variants 3 .…”

Section: Introductionmentioning

confidence: 99%

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P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa

McCulloch¹

2018

Preprint

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The PfATP4 (PF3D7 1211900) multi-drug resistance mutation G223R is found in Africa by genetically analyzing 2640 worldwide Plasmodium falciparum blood stage isolates (the Ma-lariaGen Pf3k resource). This mutation confers an approximate 8 fold [4] increase in the PfATP4 IC 50 of Spiroindolones (KAE609 & KAE678) [14],[16],[4],[10] and Aminopyrazoles (GNF-Pf4492) [4]. It is postulated that the G223R mutation may be a consequence of the drug resistant Southeast Asian Dd2 genotype becoming more dominant in Africa [3]. The presence of this mutation has important policy implications for the eventual general deployment of the Spiroindolone KAE609 (Cipargamin) which is currently undergoing stage 2 clinical trials.

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Section: Introductioncontrasting

confidence: 99%

Section: Introductioncontrasting

confidence: 70%

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P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa

McCulloch¹

2018

Preprint

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“…Antimalarial drug resistance represents a major focus of research for many partner studies within the Pf Community Project, and this dataset therefore contains a significant body of data that have appeared in previous reports on drug resistance. Readers are referred to these publications for more detailed analyses of local patterns of resistance [9][10][11][12][13][14][16][17][18][19][20][21][22] and of resistance to specific drugs including chloroquine 16,21 , sulfadoxine-pyrimethamine 16,19,21 and artemisinin combination therapy [9][10][11][13][14][15]17,18,21,22 .…”

Section: Classification Of Samples Based On Markers Of Drug Resistancementioning

confidence: 99%

“…9 Data produced by the Pf Community Project have been used to address a broad range of research questions, both by the groups that generated samples and data and by the wider research community, and have generated over 50 previous publications (refs . These data have become a key resource for the epidemiology and population genetics of antimalarial drug resistance [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and an important platform for the discovery of new genetic markers and mechanisms of resistance through genome-wide association studies [23][24][25][26][27] and combined genome-transcriptome analysis. 28 The data have also been used to study gene deletions that cause failure of rapid diagnostic tests 29 ; to characterise genetic variation in malaria vaccine antigens 30,31 ; to screen for new vaccine candidates 32 ; to investigate specific host-parasite interactions 33,34 ; and to describe the evolutionary adaptation and diversification of local parasite populations.…”

Section: Introductionmentioning

confidence: 99%

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples

Pearson

Amato

Kwiatkowski

2019

Preprint

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MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination. MethodsAll samples in this study were derived from blood samples obtained from patients with P. falciparum malaria, collected with informed consent from the patient or a parent or guardian. At each location, sample collection was approved by the appropriate local and institutional ethics committees. The following local and institutional committees gave ethical approval for the partner studies:Standard laboratory protocols were used to determine DNA quantity and proportion of human DNA in each sample as previously described 7,56 .

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Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

Sepúlveda

Phelan

Benavente

et al. 2018

Infection, Genetics and Evolution

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Many rapid diagnostic tests (RDT) used on suspected malaria cases are based on the detection of the protein encoded by the Plasmodium falciparum histidine-rich protein-2 (pfhrp2) gene, which shares a high sequence homology with pfhrp3 in the 3D7 reference genome. Parasite isolates showing pfhrp2 and pfhrp3 gene deletions have been emerging over the years, but a comprehensive genetic analysis of these variants is still lacking. With this purpose, genomic data from experimental P. falciparum genetic crosses between different laboratory lines (3D7, HB3, DD2, 7G8 and GB4) were first analysed (n = 98). The frequency of pfhrp2 deletions was consistent with a Mendelian prediction in HB3 × DD2 (56.7%; 95%CI = (39.5%-72.9%)). Moreover, the pfhrp2 and pfhrp3 deletions segregated independently of each other in the same genetic cross. Analysis of 3D7 × HB3 and 7G8 × GB4 estimated the probability of spontaneously generating a pfhrp2 deletion during sexual recombination to be up to 6.2%. Next, whole genome sequence data from 1970 P. falciparum isolates collected globally were analysed. Nine samples displayed depth of coverage consistent with pfhrp2 deletions (0.5%), but the corresponding split-read analysis could not confirm deletions in seven of these samples. Twenty-eight isolates had evidence of pfhrp3 deletions (1.4%), which are widespread in Southeast Asia. Finally, a meta-analysis of published data revealed a positive mean association between the frequencies of pfhrp2 and pfhrp3 deletions in Africa and South America. This result suggested a shared selective pressure acting on these genetic variants. In conclusion, evidence of genetic selection on both pfhrp2 and pfhrp3 deletions was presented, but experimental crosses do not provide evidence of a fitness cost of these variants. Further work is urgently needed to accurately determine the prevalence and the degree of association between these genetic variants, and the respective impact on diagnostic accuracy of many in-use RDT.

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Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

Cited by 12 publications

References 17 publications

P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa

P. falciparum PfATP4 Multi-Drug Resistance Resistance to KAE609 (Cipargamin) is Present in Africa

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples

Global analysis of Plasmodium falciparum histidine-rich protein-2 (pfhrp2) and pfhrp3 gene deletions using whole-genome sequencing data and meta-analysis

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