Phylogenetic analysis suggests single and multiple origins of dihydrofolate reductase mutations in Plasmodium vivax

Shaukat, Ayaz; Ali, Qasim; Raud, Lucy; Wahab, Abdul; Khan, Taj Ali; Rashid, Imran; Rashid, Muhammad Abdul Rehman; Hussain, Mubashir; Saleem, Muhammad; Sargison, Neil; Chaudhry, Umer

doi:10.1016/j.actatropica.2020.105821

Cited by 5 publications

(9 citation statements)

References 41 publications

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“…Similarly, 21 unique cattle-derived haplotypes of the 129G (GGC), 253S (TCT) and 262S (TCA) resistance mutant demonstrated evidence of a single origin. These results contrast with those of a previous study of the evolutionary origin of human protozoan parasite P.vivax dhfr resistance-conferring mutations demonstrated evidence of a single origin of pyrimethamine resistance (Shaukat et al, 2021).…”

Section: Discussioncontrasting

confidence: 99%

“…This scenario would likely be a consequence of the gene flow of drug resistance alleles through host movement. In contrast, resistance mutations could repeatedly arise from multiple origins, become fixed by selection and migrate between parasites as a result of host movement (Chaudhry et al, 2016a; Chaudhry et al, 2015; Shaukat et al, 2019; Shaukat et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…High throughput deep amplicon sequencing using the Illumina Mi-Seq platform is an accurate and relatively low-cost method for the identification of amplicon sequence variants in parasites. The method has transformed the study of benzimidazole resistance in nematode parasites (Ali et al, 2019; Sargison et al, 2019), and pyrimethamine resistance in Plasmodium (Shaukat et al, 2019; Shaukat et al, 2021) and has the potential to open new areas of research to improve understanding of buparvaquone resistance in Theileria . The method can generate sequence reads up to 600 bp in length by targeting primer binding to conserved sites.…”

Section: Introductionmentioning

confidence: 99%

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Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in ruminants

Ali

Zahid

Mhadhbi

et al. 2022

Preprint

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Control of tropical theileriosis depends on the use of a single drug, buparvaquone, the efficacy of which is compromised by the emergence of resistance. The present study was undertaken to improve understanding of the role of mutations conferring buparvaquone resistance in Theileria annulata, and the effects of selection pressures on their emergence and spread. First, we investigated genetic characteristics of the cytochrome b locus associated with buparvaquone resistance in 10 susceptible and 7 resistant T. annulata isolates. The 129G (GGC) mutation was found in the Q01 binding pocket and 253S (TCT) and 262S (TCA) mutations were identified within the Q02 binding pocket. Next, we examined field isolates and identified cytochrome b mutations 129G (GGC), 253S (TCT) and 262S (TCA) in 21/75 buffalo-derived and 19/119 cattle-derived T. annulata isolates, providing evidence of positive selection pressure. Both hard and soft selective sweeps were identified, with striking differences between isolates. For example, 19 buffalo-derived and 7 cattle-derived isolates contained 129G (GGC) and 253S (TCT) resistance haplotypes at a high frequency, implying the emergence of resistance by a single mutation. Two buffalo-derived and 11 cattle-derived isolates contained equally high frequencies of 129G (GGC), 253S (TCT), 129G (GGC)/253S (TCT) and 262S (TCA) resistance haplotypes, implying the emergence of resistance by pre-existing and or recurrent mutations. Phylogenetic analysis further revealed that 9 and 21 unique haplotypes in buffalo and cattle-derived isolates were present in a single lineage, suggesting a single origin. We propose that animal migration between farms is an important factor in the spread of buparvaquone resistance in endemic regions of Pakistan. The overall outcomes will be useful in understanding how drug resistance emerges and spreads, and this information will help design strategies to optimise the use and lifespan of the single most drug use to control tropical theileriosis.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in ruminants

Ali

Zahid

Mhadhbi

et al. 2022

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“…They found multiple origins of the double PvDHFR mutant 58R,117N and three independent origins of triple mutant 58R,61M,117T and quadruple mutants 57I,61M,117T,173F and 57L,58R,61M,117T in Thailand, Indonesia and Papua New Guinea/Vanuatu. Shaukat et al (2021) [79] assessed the evolutionary origin of PvDHFR pyrimethamine resistance mutations in Punjab, Pakistan and found multiple origins of single mutation S117N and a common origin of double mutant 58R,S117N and triple mutants 57L,58R,117N, 58R,61M,117N and 58R,118N,I173L. This is in contrast to the evolutionary origin of pyrimethamine resistance in PfDHFR, where mutations in Africa shared a common origin with a resistance lineage from Asia.…”

Section: Oguike Et Al (2016)mentioning

confidence: 99%

“…[70] investigated isolates from Colombia, India, Indonesia, Papua New Guinea, Sri Lanka, Thailand and Vanuatu. They found multiple origins of the double PvDHFR mutant 58R,117N and three independent origins of triple mutant 58R,61M,117T and quadruple mutants 57I,61M,117T,173F and 57L,58R,61M,117T in Thailand, Indonesia and Papua New Guinea/Vanuatu Shaukat et al (2021) [71]. assessed the evolutionary origin of PvDHFR pyrimethamine resistance mutations in Punjab, Pakistan and found multiple origins of single mutation S117N and a common origin of double mutant 58R,S117N and triple mutants 57L,58R,117N, 58R,61M,117N and 58R,118N,I173L.…”

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A computational method for predicting the most likely evolutionary trajectories in the step-wise accumulation of resistance mutations

Eccleston

Mańko

Campino

et al. 2022

Preprint

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Pathogen evolution of drug resistance often occurs in a stepwise manner via accumulation of multiple mutations, which in combination have a non-additive impact on fitness, a phenomenon known as epistasis. Epistasis complicates the sequence-structure-function relationship and undermines our ability to predict evolution. We present a computational method to predict evolutionary trajectories that accounts for epistasis, using the Rosetta Flex ddG protocol to estimate drug binding free energy changes upon mutation and an evolutionary model based in thermodynamics and statistical mechanics. We apply this method to predict evolutionary trajectories to known multiple mutations associated with resistant phenotypes in malaria. Resistance to the combination drug sulfadoxine-pyrimethamine (SP) in malaria-causing species Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) has arisen via the accumulation of multiple point mutations in the DHFR and DHPS genes. Four known PfDHFR pyrimethamine resistance mutations are highly prevalent in field-isolates and multiple studies have shown epistatic interactions between these mutations determine the accessible evolutionary trajectories to the highly resistant quadruple mutation N51I,C59R,S108N,I164L. We simulated the possible evolutionary trajectories to this quadruple PfDHFR mutation as well as the homologous PvDHFR mutations. In both cases, our most probable pathways agreed well with those determined experimentally. We also applied this method to predict the most likely evolutionary pathways to observed multiple mutations associated with sulfadoxine resistance in PfDHPS and PvDHPS. This novel method can be applied to any drug-target system where the drug acts by binding to the target.

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Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in bovine

Qasim

Zahid

Mhadhbi

et al. 2022

International Journal for Parasitology: Drugs and Drug Resistan

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Phylogenetic analysis suggests single and multiple origins of dihydrofolate reductase mutations in Plasmodium vivax

Cited by 5 publications

References 41 publications

Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in ruminants

Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in ruminants

A computational method for predicting the most likely evolutionary trajectories in the step-wise accumulation of resistance mutations

Genetic characterisation of the Theileria annulata cytochrome b locus and its impact on buparvaquone resistance in bovine

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