CoChat
Sign Up
PreprintCited by 15Malaria Research and ControlPhytochemical compounds biological activitiesPharmacogenetics and Drug Metabolism

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Population genomics and transcriptomics of Plasmodium falciparum uncover components of the artemisinin resistance genetic background.

Open access
Bozdech, Zbynek, Nayak, Sourav, Kucharski, Michal, Tien, Quang Huy Duong, Roca, Xavier, Peto, Thomas, Tripura, Rupam, Callery, James, Pluijm, Rob van der, Vongpromek, Ranitha, Miotto, Olivo, Mukaka, Mavuto, von Seidlein, Lorenz, Dhorda, Mehul, Imwong, Mallika, Day, Nicholas, White, Nicholas, Dondorp, Arjen, Lek, Dysoley, Ho, Nghia, Nguyen, Dong, Le, Thanh Long, Rekol, Huy, Nguyen, Hoang Chau·2023·Nature Communications
DOI 10.21203/rs.3.rs-3404050/v1PMC PMC11621345

Preprint — published as 10.1038/s41467-024-54915-6 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

The emergence and spread of Plasmodium falciparum lineages resistant to artemisinins is threatening the efficacy of Artemisinin Combination Therapies (ACTs), the global first-line treatment for falciparum malaria. Artemisinin resistance is a complex genetic trait in which nonsynonymous SNPs in PfK13 cooperate with other, currently unknown, genetic variations to mediate the resistance phenotype. To identify these new molecular factors, we carried out population genomic/transcriptomic analyses of P. falciparum collected from patients with uncomplicated malaria in Cambodia and Vietnam between 2018 and 2020. GWAS confirmed the strong association of mutations in PfK13, in particular C580Y, with artemisinin resistance, but also uncovered significant associations with several additional polymorphisms, including PfRad5 in which two nonsynonymous mutations (N1131I and N821K) were independently associated with artemisinin resistance since its emergence. In addition, an intronic SNP in the gene encoding a WD40 repeat-containing protein on chromosome 11 (PfWD11) was associated. Population transcriptome analyses revealed a defined set of genes whose steady-state levels of mRNA and/or alternatively spliced or antisense transcripts correlated with artemisinin resistance. Using transcriptomics of sequential parasite samples after the start of ACT treatment, we also characterized in vivo transcriptional responses to artemisinins and demonstrated the capacity of the resistant parasites to decelerate their intraerythrocytic developmental cycle, which can contribute to the resistant phenotype. During this process, both PfRAD5 and PfWD11 appear to upregulate an alternatively spliced isoform suggesting a contribution to the protective response to artemisinins. Comparison with historical samples indicated that PfRad5 and PfWD11 have been under selective pressure since the emergence of artemisinin resistance in the Greater Mekong Subregion as covariates of PfK13. Hence both genes now represent new high-confidence markers presumably as the key elements of the artemisinin resistance genetic background.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.21203/rs.3.rs-3404050/v1

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 90

  1. Dondorp, A. M. et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361, 455–467 (2009). https://doi.org:10.1056/NEJMoa0808859 · DOI · Paper page
  2. Noedl, H. et al. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med 359, 2619–2620 (2008). https://doi.org:10.1056/NEJMc0805011 · DOI
  3. Jacob, C. G. et al. Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination. Elife 10 (2021). https://doi.org:10.7554/eLife.62997 · DOI
  4. Conrad, M. D. et al. Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda. N Engl J Med 389, 722–732 (2023). https://doi.org:10.1056/NEJMoa2211803 · DOI
  5. Fidock, D. A. & Rosenthal, P. J. Artemisinin resistance in Africa: How urgent is the threat? Med 2, 1287–1288 (2021). https://doi.org:10.1016/j.medj.2021.11.005 · DOI
  6. Ashley, E. A. et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 371, 411–423 (2014). https://doi.org:10.1056/NEJMoa1314981 · DOI · Paper page
  7. Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505, 50–55 (2014). https://doi.org:10.1038/nature12876 · DOI
  8. Straimer, J. et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347, 428–431 (2015). https://doi.org:10.1126/science.1260867 · DOI
  9. Uwimana, A. et al. Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. Lancet Infect Dis 21, 1120–1128 (2021). https://doi.org:10.1016/S1473-3099(21)00142-0 · DOI
  10. Asua, V. et al. Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda. J Infect Dis 223, 985–994 (2021). https://doi.org:10.1093/infdis/jiaa687 · DOI
  11. Balikagala, B. et al. Evidence of Artemisinin-Resistant Malaria in Africa. N Engl J Med 385, 1163–1171 (2021). https://doi.org:10.1056/NEJMoa2101746 · DOI
  12. Ndwiga, L. et al. A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa. Int J Parasitol Drugs Drug Resist 16, 155–161 (2021). https://doi.org:10.1016/j.ijpddr.2021.06.001 · DOI
  13. Chenet, S. M. et al. Independent Emergence of the Plasmodium falciparum Kelch Propeller Domain Mutant Allele C580Y in Guyana. J Infect Dis 213, 1472–1475 (2016). https://doi.org:10.1093/infdis/jiv752 · DOI
  14. Mathieu, L. C. et al. Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance. Elife 9 (2020). https://doi.org:10.7554/eLife.51015 · DOI
  15. Takala-Harrison, S. et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis 211, 670–679 (2015). https://doi.org:10.1093/infdis/jiu491 · DOI
  16. Woodrow, C. J. & White, N. J. The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. FEMS Microbiol Rev 41, 34–48 (2017). https://doi.org:10.1093/femsre/fuw037 · DOI
  17. Miotto, O. et al. Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet 45, 648–655 (2013). https://doi.org:10.1038/ng.2624 · DOI
  18. Miotto, O. et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet 47, 226–234 (2015). https://doi.org:10.1038/ng.3189 · DOI
  19. Cheeseman, I. H. et al. A major genome region underlying artemisinin resistance in malaria. Science 336, 79–82 (2012). https://doi.org:10.1126/science.1215966 · DOI
  20. Takala-Harrison, S. et al. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia. Proc Natl Acad Sci U S A 110, 240–245 (2013). https://doi.org:10.1073/pnas.1211205110 · DOI
  21. Cerqueira, G. C. et al. Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance. Genome Biol 18, 78 (2017). https://doi.org:10.1186/s13059-017-1204-4 · DOI
  22. Mok, S. et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 347, 431–435 (2015). https://doi.org:10.1126/science.1260403 · DOI
  23. Mok, S. et al. Artemisinin resistance in Plasmodium falciparum is associated with an altered temporal pattern of transcription. BMC Genomics 12, 391 (2011). https://doi.org:10.1186/1471-2164-12-391 · DOI
  24. Zhu, L. et al. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Commun Biol 5, 274 (2022). https://doi.org:10.1038/s42003-022-03215-0 · DOI
  25. Zhu, L. et al. The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background. Nat Commun 9, 5158 (2018). https://doi.org:10.1038/s41467-018-07588-x · DOI
  26. Kucharski, M. et al. Short tandem repeat polymorphism in the promoter region of cyclophilin 19B drives its transcriptional upregulation and contributes to drug resistance in the malaria parasite Plasmodium falciparum. PLoS Pathog 19, e1011118 (2023). https://doi.org:10.1371/journal.ppat.1011118 · DOI
  27. Rosenthal, M. & Ng, C. Parasite proteostasis and artemisinin resistance. Res Sq (2023). https://doi.org:10.21203/rs.3.rs-2926003/v1 · DOI
  28. Rosenthal, M. R. & Ng, C. L. Plasmodium falciparum Artemisinin Resistance: The Effect of Heme, Protein Damage, and Parasite Cell Stress Response. ACS Infect Dis 6, 1599–1614 (2020). https://doi.org:10.1021/acsinfecdis.9b00527 · DOI
  29. Talman, A. M., Clain, J., Duval, R., Menard, R. & Ariey, F. Artemisinin Bioactivity and Resistance in Malaria Parasites. Trends Parasitol 35, 953–963 (2019). https://doi.org:10.1016/j.pt.2019.09.005 · DOI
  30. Tilley, L., Straimer, J., Gnadig, N. F., Ralph, S. A. & Fidock, D. A. Artemisinin Action and Resistance in Plasmodium falciparum. Trends Parasitol 32, 682–696 (2016). https://doi.org:10.1016/j.pt.2016.05.010 · DOI
  31. Birnbaum, J. et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science 367, 51–59 (2020). https://doi.org:10.1126/science.aax4735 · DOI
  32. Oberstaller, J. et al. Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum. Int J Parasitol Drugs Drug Resist 16, 119–128 (2021). https://doi.org:10.1016/j.ijpddr.2021.05.006 · DOI
  33. Simmons, C. F. et al. Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum. Sci Rep 13, 399 (2023). https://doi.org:10.1038/s41598-023-27417-6 · DOI
  34. Demas, A. R. et al. Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. Proc Natl Acad Sci U S A 115, 12799–12804 (2018). https://doi.org:10.1073/pnas.1812317115 · DOI
  35. Delandre, O. et al. Absence of association between polymorphisms in the pfcoronin and pfk13 genes and the presence of Plasmodium falciparum parasites after treatment with artemisinin derivatives in Senegal. Int J Antimicrob Agents 56, 106190 (2020). https://doi.org:10.1016/j.ijantimicag.2020.106190 · DOI
  36. Sharma, A. I., Demas, A. R., Hartl, D. L. & Wirth, D. F. Reply to Velavan et al.: Polymorphisms of pfcoronin in natural populations: Implications for functional significance. Proc Natl Acad Sci U S A 116, 12613–12614 (2019). https://doi.org:10.1073/pnas.1907920116 · DOI
  37. Velavan, T. P., Nderu, D., Agbenyega, T., Ntoumi, F. & Kremsner, P. G. An alternative dogma on reduced artemisinin susceptibility: A new shadow from east to west. Proc Natl Acad Sci U S A 116, 12611–12612 (2019). https://doi.org:10.1073/pnas.1907142116 · DOI
  38. Sharma, A. I. et al. Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum. PLoS Genet 16, e1009266 (2020). https://doi.org:10.1371/journal.pgen.1009266 · DOI
  39. Gnadig, N. F. et al. Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13. PLoS Pathog 16, e1008482 (2020). https://doi.org:10.1371/journal.ppat.1008482 · DOI
  40. Leber, W. et al. A unique phosphatidylinositol 4-phosphate 5-kinase is activated by ADP-ribosylation factor in Plasmodium falciparum. Int J Parasitol 39, 645–653 (2009). https://doi.org:10.1016/j.ijpara.2008.11.015 · DOI
  41. Rocamora, F. et al. Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLoS Pathog 14, e1006930 (2018). https://doi.org:10.1371/journal.ppat.1006930 · DOI
  42. Tinto-Font, E. et al. A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures. Nat Microbiol 6, 1163–1174 (2021). https://doi.org:10.1038/s41564-021-00940-w · DOI
  43. Miao, J. et al. The MYST family histone acetyltransferase regulates gene expression and cell cycle in malaria parasite Plasmodium falciparum. Mol Microbiol 78, 883–902 (2010). https://doi.org:10.1111/j.1365-2958.2010.07371.x · DOI
  44. Zhang, M. et al. The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite. Nat Commun 12, 4563 (2021). https://doi.org:10.1038/s41467-021-24814-1 · DOI
  45. Mok, S. et al. Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival. Nat Commun 12, 530 (2021). https://doi.org:10.1038/s41467-020-20805-w · DOI
  46. Hamilton, W. L. et al. Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study. Lancet Infect Dis 19, 943–951 (2019). https://doi.org:10.1016/S1473-3099(19)30392-5 · DOI
  47. Peto, T. J. et al. Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial. Lancet Infect Dis 22, 867–878 (2022). https://doi.org:10.1016/S1473-3099(21)00692-7 · DOI
  48. Imwong, M. et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis 17, 491–497 (2017). https://doi.org:10.1016/S1473-3099(17)30048-8 · DOI
  49. Amato, R. et al. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect Dis 17, 164–173 (2017). https://doi.org:10.1016/S1473-3099(16)30409-1 · DOI
  50. Witkowski, B. et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect Dis 17, 174–183 (2017). https://doi.org:10.1016/S1473-3099(16)30415-7 · DOI
  51. Kang, Y. J. et al. CPC2: a fast and accurate coding potential calculator based on sequence intrinsic features. Nucleic Acids Res 45, W12-W16 (2017). https://doi.org:10.1093/nar/gkx428 · DOI
  52. MalariaGen et al. Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples. Wellcome Open Res 8, 22 (2023). https://doi.org:10.12688/wellcomeopenres.18681.1 · DOI
  53. Muller, O., Lu, G. Y. & von Seidlein, L. Geographic expansion of artemisinin resistance. J Travel Med 26 (2019). https://doi.org:10.1093/jtm/taz030 · DOI
  54. van der Pluijm, R. W. et al. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: a multicentre, open-label, randomised clinical trial. Lancet 395, 1345–1360 (2020). https://doi.org:10.1016/S0140-6736(20)30552-3 · DOI
  55. Imwong, M. et al. Molecular epidemiology of resistance to antimalarial drugs in the Greater Mekong subregion: an observational study. Lancet Infect Dis 20, 1470–1480 (2020). https://doi.org:10.1016/S1473-3099(20)30228-0 · DOI
  56. Elserafy, M., Abugable, A. A., Atteya, R. & El-Khamisy, S. F. Rad5, HLTF, and SHPRH: A Fresh View of an Old Story. Trends Genet 34, 574–577 (2018). https://doi.org:10.1016/j.tig.2018.04.006 · DOI
  57. Gibbons, J. et al. Altered expression of K13 disrupts DNA replication and repair in Plasmodium falciparum. BMC Genomics 19, 849 (2018). https://doi.org:10.1186/s12864-018-5207-7 · DOI
  58. Goyal, M. et al. An SR protein is essential for activating DNA repair in malaria parasites. J Cell Sci 134 (2021). https://doi.org:10.1242/jcs.258572 · DOI
  59. Gupta, D. K., Patra, A. T., Zhu, L., Gupta, A. P. & Bozdech, Z. DNA damage regulation and its role in drug-related phenotypes in the malaria parasites. Sci Rep 6, 23603 (2016). https://doi.org:10.1038/srep23603 · DOI
  60. Maneekesorn, S. et al. Deletion of Plasmodium falciparum ubc13 increases parasite sensitivity to the mutagen, methyl methanesulfonate and dihydroartemisinin. Sci Rep 11, 21791 (2021). https://doi.org:10.1038/s41598-021-01267-6 · DOI
  61. Piao, S. et al. ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells. Autophagy 13, 2056–2071 (2017). https://doi.org:10.1080/15548627.2017.1377377 · DOI
  62. Dogovski, C. et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol 13, e1002132 (2015). https://doi.org:10.1371/journal.pbio.1002132 · DOI
  63. Meshnick, S. R. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 32, 1655–1660 (2002). https://doi.org:10.1016/s0020-7519(02)00194-7 · DOI
  64. Lee, Y. & Rio, D. C. Mechanisms and Regulation of Alternative Pre-mRNA Splicing. Annu Rev Biochem 84, 291–323 (2015). https://doi.org:10.1146/annurev-biochem-060614-034316 · DOI · Paper page
  65. Hoeijmakers, W. A. M. et al. Epigenetic reader complexes of the human malaria parasite, Plasmodium falciparum. Nucleic Acids Res 47, 11574–11588 (2019). https://doi.org:10.1093/nar/gkz1044 · DOI
  66. Callebaut, I., Prat, K., Meurice, E., Mornon, J. P. & Tomavo, S. Prediction of the general transcription factors associated with RNA polymerase II in Plasmodium falciparum: conserved features and differences relative to other eukaryotes. BMC Genomics 6, 100 (2005). https://doi.org:10.1186/1471-2164-6-100 · DOI
  67. Uwimana, A. et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nat Med 26, 1602–1608 (2020). https://doi.org:10.1038/s41591-020-1005-2 · DOI
  68. Kayiba, N. K. et al. Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review. Lancet Infect Dis 21, e82-e92 (2021). https://doi.org:10.1016/S1473-3099(20)30493-X · DOI
  69. Stokes, B. H. et al. Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. Elife 10 (2021). https://doi.org:10.7554/eLife.66277 · DOI
  70. Li, Y., Baptista, R. P. & Kissinger, J. C. Noncoding RNAs in Apicomplexan Parasites: An Update. Trends Parasitol 36, 835–849 (2020). https://doi.org:10.1016/j.pt.2020.07.006 · DOI
  71. Simantov, K., Goyal, M. & Dzikowski, R. Emerging biology of noncoding RNAs in malaria parasites. PLoS Pathog 18, e1010600 (2022). https://doi.org:10.1371/journal.ppat.1010600 · DOI
  72. Yeoh, L. M., Lee, V. V., McFadden, G. I. & Ralph, S. A. Alternative Splicing in Apicomplexan Parasites. mBio 10 (2019). https://doi.org:10.1128/mBio.02866-18 · DOI
  73. Vembar, S. S., Scherf, A. & Siegel, T. N. Noncoding RNAs as emerging regulators of Plasmodium falciparum virulence gene expression. Curr Opin Microbiol 20, 153–161 (2014). https://doi.org:10.1016/j.mib.2014.06.013 · DOI
  74. Kafsack, B. F. et al. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature 507, 248–252 (2014). https://doi.org:10.1038/nature12920 · DOI
  75. Yeoh, L. M. et al. Alternative splicing is required for stage differentiation in malaria parasites. Genome Biol 20, 151 (2019). https://doi.org:10.1186/s13059-019-1756-6 · DOI
  76. Bunnik, E. M. et al. Polysome profiling reveals translational control of gene expression in the human malaria parasite Plasmodium falciparum. Genome Biol 14, R128 (2013). https://doi.org:10.1186/gb-2013-14-11-r128 · DOI
  77. Kucharski, M. et al. A comprehensive RNA handling and transcriptomics guide for high-throughput processing of Plasmodium blood-stage samples. Malar J 19, 363 (2020). https://doi.org:10.1186/s12936-020-03436-w · DOI
  78. Chomczynski, P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. Biotechniques 15, 532–534, 536–537 (1993).
  79. van der Pluijm, R. W. et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis 19, 952–961 (2019). https://doi.org:10.1016/S1473-3099(19)30391-3 · DOI
  80. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009). https://doi.org:10.1093/bioinformatics/btp324 · DOI · Paper page
  81. Miles, A. et al. Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum. Genome Res 26, 1288–1299 (2016). https://doi.org:10.1101/gr.203711.115 · DOI
  82. Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics 43, 11 10 11–11 10 33 (2013). https://doi.org:10.1002/0471250953.bi1110s43 · DOI · Paper page
  83. Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015). https://doi.org:10.1186/s13742-015-0047-8 · DOI · Paper page
  84. Paradis, E. & Schliep, K. ape 5.0: an environment for modern phylogenetics and evolutionary analyses in R. Bioinformatics 35, 526–528 (2019). https://doi.org:10.1093/bioinformatics/bty633 · DOI
  85. Danecek, P. et al. The variant call format and VCFtools. Bioinformatics 27, 2156–2158 (2011). https://doi.org:10.1093/bioinformatics/btr330 · DOI
  86. Alexander, D. H., Novembre, J. & Lange, K. Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19, 1655–1664 (2009). https://doi.org:10.1101/gr.094052.109 · DOI · Paper page
  87. Lippert, C. et al. FaST linear mixed models for genome-wide association studies. Nat Methods 8, 833–835 (2011). https://doi.org:10.1038/nmeth.1681 · DOI · Paper page
  88. Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat Methods 12, 357–360 (2015). https://doi.org:10.1038/nmeth.3317 · DOI · Paper page
  89. Pertea, M. et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33, 290–295 (2015). https://doi.org:10.1038/nbt.3122 · DOI
  90. Varadi, M. et al. AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res 50, D439-D444 (2022). https://doi.org:10.1093/nar/gkab1061 · DOI · Paper page

Metadata

Authors
Bozdech, Z., Nayak, S., Kucharski, M., Tien, Q. H. D., Roca, X., Peto, T., Tripura, R., Callery, J., Pluijm, R. V. D., Vongpromek, R., Miotto, O., Mukaka, M., von Seidlein, L., Dhorda, M., Imwong, M., Day, N., White, N., Dondorp, A., Lek, D., Ho, N., Nguyen, D., Le, T. L., Rekol, H., & Nguyen, H. C.
Affiliations
  • Nanyang Technological University (SG)
  • Mahidol University (TH)
  • Mahidol Oxford Tropical Medicine Research Unit
  • Pham Ngoc Thach University of Medicine (VN)
  • Cambodia National Malaria Center (KH)
  • 6Oxford University Clinical Research Unit, Hospital for Tropical Diseases,
  • 10Khanh Hoa Hospital for Tropical diseases, Khanh Hoa province
  • 11Phuoc Long Hospital, Binh Phuoc province
  • 4Centre for Parasitology, Entomology and Malaria Control,
  • 6Oxford University Clinical Research Unit, Hospital for Tropical Diseases
Corresponding author
  • Bozdech, Zbynek
  • Dondorp, Arjen
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-20
Volume
15
Issue
1
Pages
10625-10625
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-3404050/v1
PMC
PMC11621345
OpenAlex
W4405056416
Cited by
15
References
1
Citations by year
2026: 6 · 2025: 6 · 2024: 3
FWCI
6.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DR-NTU (Nanyang Technological University) (publishedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ministry of Education - Singapore (#MOE2019-T3-1-007)
  • Ministry of Education, India
  • Medical Research Council
  • National Medical Research Council
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Phytochemical compounds biological activities
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
Plasmodium falciparum, artemisinin resistance, pfk13, non-synonymous SNPs, alternative splicing, antisense transcripts, intraerythrocytic developmental cycle, selection pressure, Greater Mekong Subregion, uncomplicated malaria, Cambodia, Vietnam
MeSH terms
Antimalarials, Cambodia, Drug Resistance, Humans, Plasmodium falciparum, Vietnam, Protozoan Proteins, Malaria, Falciparum, Polymorphism, Single Nucleotide, Gene Expression Profiling, Genomics, Artemisinins, Transcriptome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review