A molecular barcode to inform the geographical origin and transmission dynamics of Plasmodium vivax malaria

Autoři: Ernest Diez Benavente aff001;  Monica Campos aff001;  Jody Phelan aff001;  Debbie Nolder aff001;  Jamille G. Dombrowski aff002;  Claudio R. F. Marinho aff002;  Kanlaya Sriprawat aff003;  Aimee R. Taylor aff004;  James Watson aff006;  Cally Roper aff001;  Francois Nosten aff003;  Colin J. Sutherland aff001;  Susana Campino aff001;  Taane G. Clark aff001
Působiště autorů: Faculty of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom aff001;  Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil aff002;  Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Tak, Thailand aff003;  Harvard T.H. Chan School of Public Health, Department of Epidemiology, Boston, Massachusetts, United States of America aff004;  Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America aff005;  Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine Research Building, University of Oxford Old Road Campus, Oxford, United Kingdom aff006;  Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand aff007;  Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom aff008
Vyšlo v časopise: A molecular barcode to inform the geographical origin and transmission dynamics of Plasmodium vivax malaria. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008576
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008576


Although Plasmodium vivax parasites are the predominant cause of malaria outside of sub-Saharan Africa, they not always prioritised by elimination programmes. P. vivax is resilient and poses challenges through its ability to re-emerge from dormancy in the human liver. With observed growing drug-resistance and the increasing reports of life-threatening infections, new tools to inform elimination efforts are needed. In order to halt transmission, we need to better understand the dynamics of transmission, the movement of parasites, and the reservoirs of infection in order to design targeted interventions. The use of molecular genetics and epidemiology for tracking and studying malaria parasite populations has been applied successfully in P. falciparum species and here we sought to develop a molecular genetic tool for P. vivax. By assembling the largest set of P. vivax whole genome sequences (n = 433) spanning 17 countries, and applying a machine learning approach, we created a 71 SNP barcode with high predictive ability to identify geographic origin (91.4%). Further, due to the inclusion of markers for within population variability, the barcode may also distinguish local transmission networks. By using P. vivax data from a low-transmission setting in Malaysia, we demonstrate the potential ability to infer outbreak events. By characterising the barcoding SNP genotypes in P. vivax DNA sourced from UK travellers (n = 132) to ten malaria endemic countries predominantly not used in the barcode construction, we correctly predicted the geographic region of infection origin. Overall, the 71 SNP barcode outperforms previously published genotyping methods and when rolled-out within new portable platforms, is likely to be an invaluable tool for informing targeted interventions towards elimination of this resilient human malaria.

Klíčová slova:

Asia – Genomics – Malaria – Molecular genetics – Phylogenetic analysis – Plasmodium – principal component analysis – Trees


1. Howes RE, Battle KE, Mendis KN, Smith DL, Cibulskis RE, Baird JK, et al. Global Epidemiology of Plasmodium vivax. Am J Trop Med Hyg. 2016;95: 15–34. doi: 10.4269/ajtmh.16-0141 27402513

2. WHO. World Malaria Report 2017. Geneva; 2017.

3. Tjitra E, Anstey NM, Sugiarto P, Warikar N, Kenangalem E, Karyana M, et al. Multidrug-Resistant Plasmodium vivax Associated with Severe and Fatal Malaria: A Prospective Study in Papua, Indonesia. PLOS Med. 2008;5: e128. Available: https://doi.org/10.1371/journal.pmed.0050128 18563962

4. Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Warikar N, Seal A, et al. Adverse Pregnancy Outcomes in an Area Where Multidrug-Resistant Plasmodium vivax and Plasmodium falciparum Infections Are Endemic. Clin Infect Dis. 2008;46: 1374–1381. doi: 10.1086/586743 18419439

5. Poespoprodjo JR, Fobia W, Kenangalem E, Lampah DA, Hasanuddin A, Warikar N, et al. Vivax Malaria: A Major Cause of Morbidity in Early Infancy. Clin Infect Dis. 2009;48: 1704–1712. Available: http://dx.doi.org/10.1086/599041 19438395

6. Price RN, von Seidlein L, Valecha N, Nosten F, Baird JK, White NJ. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. Lancet Infect Dis. 2014;14: 982–991. doi: 10.1016/S1473-3099(14)70855-2 25213732

7. Menard D, Dondorp A. Antimalarial Drug Resistance: A Threat to Malaria Elimination. Cold Spring Harb Perspect Med. 2017;7. Available: http://perspectivesinmedicine.cshlp.org/content/7/7/a025619.abstract

8. Cotter C, Sturrock HJW, Hsiang MS, Liu J, Phillips AA, Hwang J, et al. The changing epidemiology of malaria elimination: new strategies for new challenges. Lancet (London, England). 2013;382: 900–911. doi: 10.1016/S0140-6736(13)60310-4

9. Sattabongkot J, Tsuboi T, Zollner GE, Sirichaisinthop J, Cui L. Plasmodium vivax transmission: chances for control? Trends Parasitol. 2004;20: 192–198. doi: 10.1016/j.pt.2004.02.001 15099559

10. Auburn S, Benavente ED, Miotto O, Pearson RD, Amato R, Grigg MJ, et al. Genomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics. Nat Commun. 2018;9. doi: 10.1038/s41467-018-04965-4 29968722

11. Spanakos G, Snounou G, Pervanidou D, Alifrangis M, Rosanas-Urgell A, Baka A, et al. Genetic Spatiotemporal Anatomy of Plasmodium vivax Malaria Episodes in Greece, 2009–2013. Emerg Infect Dis. 2018;24: 541–548. doi: 10.3201/eid2403.170605 29460743

12. Winter DJ, Pacheco MA, Vallejo AF, Schwartz RS, Arevalo-Herrera M, Herrera S, et al. Whole Genome Sequencing of Field Isolates Reveals Extensive Genetic Diversity in Plasmodium vivax from Colombia. PLoS Negl Trop Dis. 2016;9: e0004252. Available: https://doi.org/10.1371/journal.pntd.0004252

13. Parobek CM, Lin JT, Saunders DL, Barnett EJ, Lon C, Lanteri CA, et al. Selective sweep suggests transcriptional regulation may underlie Plasmodium vivax resilience to malaria control measures in Cambodia. Proc Natl Acad Sci U S A. 2016;113: E8096–E8105. doi: 10.1073/pnas.1608828113 27911780

14. Hupalo DN, Luo Z, Melnikov A, Sutton PL, Rogov P, Escalante A, et al. Population genomics studies identify signatures of global dispersal and drug resistance in Plasmodium vivax. Nat Genet. 2016;48: 953–958. Available: http://dx.doi.org/10.1038/ng.3588 27348298

15. Pearson RD, Amato R, Auburn S, Miotto O, Almagro-Garcia J, Amaratunga C, et al. Genomic analysis of local variation and recent evolution in Plasmodium vivax. Nat Genet. 2016;48: 959–964. Available: http://dx.doi.org/10.1038/ng.3599 27348299

16. de Oliveira TC, Rodrigues PT, Menezes MJ, Gonçalves-Lopes RM, Bastos MS, Lima NF, et al. Genome-wide diversity and differentiation in New World populations of the human malaria parasite Plasmodium vivax. PLoS Negl Trop Dis. 2017;11: e0005824. Available: https://doi.org/10.1371/journal.pntd.0005824 28759591

17. Abdullah NR, Barber BE, William T, Norahmad NA, Satsu UR, Muniandy PK, et al. Plasmodium vivax population structure and transmission dynamics in Sabah Malaysia. PLoS One. 2013;8: e82553. doi: 10.1371/journal.pone.0082553 24358203

18. Getachew S, To S, Trimarsanto H, Thriemer K, Clark TG, Petros B, et al. Variation in Complexity of Infection and Transmission Stability between Neighbouring Populations of Plasmodium vivax in Southern Ethiopia. PLoS One. 2015;10: e0140780. doi: 10.1371/journal.pone.0140780 26468643

19. Trimarsanto H, Benavente ED, Noviyanti R, Utami RAS, Trianty L, Pava Z, et al. VivaxGEN: An open access platform for comparative analysis of short tandem repeat genotyping data in Plasmodium vivax Populations. PLoS Negl Trop Dis. 2017;11. doi: 10.1371/journal.pntd.0005465 28362818

20. Pava Z, Noviyanti R, Handayuni I, Trimarsanto H, Trianty L, Burdam FH, et al. Genetic micro-epidemiology of malaria in Papua Indonesia: Extensive P. vivax diversity and a distinct subpopulation of asymptomatic P. falciparum infections. PLoS One. 2017;12: e0177445. doi: 10.1371/journal.pone.0177445 28498860

21. Taylor AR, Jacob PE, Neafsey DE, Buckee CO. Estimating Relatedness Between Malaria Parasites. Genetics. 2019;212: 1337–1351. doi: 10.1534/genetics.119.302120 31209105

22. Anderson TJ, Haubold B, Williams JT, Estrada-Franco JG, Richardson L, Mollinedo R, et al. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol Biol Evol. 2000;17: 1467–1482. doi: 10.1093/oxfordjournals.molbev.a026247 11018154

23. Greenhouse B, Myrick A, Dokomajilar C, Woo JM, Carlson EJ, Rosenthal PJ, et al. Validation of microsatellite markers for use in genotyping polyclonal Plasmodium falciparum infections. Am J Trop Med Hyg. 2006;75: 836–842. 17123974

24. Andrews KR, Good JM, Miller MR, Luikart G, Hohenlohe PA. Harnessing the power of RADseq for ecological and evolutionary genomics. Nat Rev Genet. 2016;17: 81–92. doi: 10.1038/nrg.2015.28 26729255

25. Manske M, Miotto O, Campino S, Auburn S, Almagro-Garcia J, Maslen G, et al. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. Nature. 2012;487: 375–379. Available: http://dx.doi.org/10.1038/nature11174 22722859

26. Diez Benavente E, Florez de Sessions P, Moon RW, Holder AA, Blackman MJ, Roper C, et al. Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations. PLOS Genet. 2017;13: e1007008. doi: 10.1371/journal.pgen.1007008 28922357

27. Daniels R, Volkman SK, Milner DA, Mahesh N, Neafsey DE, Park DJ, et al. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking. Malar J. 2008;7: 223. doi: 10.1186/1475-2875-7-223 18959790

28. Daniels RF, Schaffner SF, Wenger EA, Proctor JL, Chang H-H, Wong W, et al. Modeling malaria genomics reveals transmission decline and rebound in Senegal. Proc Natl Acad Sci. 2015;112: 7067–7072. Available: http://www.pnas.org/content/112/22/7067.abstract 25941365

29. Preston MD, Campino S, Assefa SA, Echeverry DF, Ocholla H, Amambua-Ngwa A, et al. A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains. Nat Commun. 2014;5: 4052. Available: http://dx.doi.org/10.1038/ncomms5052 24923250

30. Chang H-H, Worby CJ, Yeka A, Nankabirwa J, Kamya MR, Staedke SG, et al. THE REAL McCOIL: A method for the concurrent estimation of the complexity of infection and SNP allele frequency for malaria parasites. PLOS Comput Biol. 2017;13: e1005348. Available: https://doi.org/10.1371/journal.pcbi.1005348 28125584

31. Auburn S, Benavente ED, Miotto O, Pearson RD, Amato R, Grigg MJ, et al. Genomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics. Nat Commun. 2018;9: 2585. doi: 10.1038/s41467-018-04965-4 29968722

32. Rodrigues PT, Alves JMP, Santamaria AM, Calzada JE, Xayavong M, Parise M, et al. Using mitochondrial genome sequences to track the origin of imported plasmodium vivax infections diagnosed in the United States. Am J Trop Med Hyg. 2014;90: 1102–1108. doi: 10.4269/ajtmh.13-0588 24639297

33. Baniecki ML, Faust AL, Schaffner SF, Park DJ, Galinsky K, Daniels RF, et al. Development of a Single Nucleotide Polymorphism Barcode to Genotype Plasmodium vivax Infections. PLoS Negl Trop Dis. 2015;9: e0003539. Available: https://doi.org/10.1371/journal.pntd.0003539 25781890

34. Benavente ED, Ward Z, Chan W, Mohareb FR, Sutherland CJ, Roper C, et al. Genomic variation in Plasmodium vivax malaria reveals regions under selective pressure. PLoS One. 2017;12. doi: 10.1371/journal.pone.0177134 28493919

35. Nag S, Dalgaard MD, Kofoed P-E, Ursing J, Crespo M, Andersen LO, et al. High throughput resistance profiling of Plasmodium falciparum infections based on custom dual indexing and Illumina next generation sequencing-technology. Sci Rep. 2017;7. doi: 10.1038/s41598-017-02724-x 28546554

36. Rumaseb A, Marfurt J, Anstey NM, Price RN, Auburn S, Barber B, et al. Genomic Analysis of Plasmodium vivax in Southern Ethiopia Reveals Selective Pressures in Multiple Parasite Mechanisms. 2019. doi: 10.1093/infdis/jiz016 30668735

37. Xu Z, Kaplan NL, Taylor JA. TAGster: efficient selection of LD tag SNPs in single or multiple populations. Bioinformatics. 2007;23: 3254–3255. doi: 10.1093/bioinformatics/btm426 17827206

38. Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC, Dondorp AM, et al. Independent Emergence of Artemisinin Resistance Mutations Among Plasmodium falciparum in Southeast Asia. J Infect Dis. 2014;211: 670–679. doi: 10.1093/infdis/jiu491 25180241

39. Vali U, Einarsson A, Waits L, Ellegren H. To what extent do microsatellite markers reflect genome-wide genetic diversity in natural populations? Mol Ecol. 2008;17: 3808–3817. doi: 10.1111/j.1365-294X.2008.03876.x 18647238

40. Thompson EA. The estimation of pairwise relationships. Ann Hum Genet. 1975;39: 173–188. doi: 10.1111/j.1469-1809.1975.tb00120.x 1052764

41. Díaz-Uriarte R, de Andrés S. Gene selection and classification of microarray data using random forest. BMC Bioinformatics. 2006;7: 3. doi: 10.1186/1471-2105-7-3 16398926

42. Chen X, Ishwaran H. Random Forests for Genomic Data Analysis. Genomics. 2012;99: 323–329. doi: 10.1016/j.ygeno.2012.04.003 22546560

43. Bright AT, Alenazi T, Shokoples S, Tarning J, Paganotti GM, White NJ, et al. Genetic analysis of primaquine tolerance in a patient with relapsing vivax malaria. Emerg Infect Dis. 2013;19: 802–805. doi: 10.3201/eid1905.121852 23648098

44. Bright AT, Manary MJ, Tewhey R, Arango EM, Wang T, Schork NJ, et al. A high resolution case study of a patient with recurrent Plasmodium vivax infections shows that relapses were caused by meiotic siblings. PLoS Negl Trop Dis. 2014;8: e2882–e2882. doi: 10.1371/journal.pntd.0002882 24901334

45. Daher A, Silva JCAL, Stevens A, Marchesini P, Fontes CJ, Ter Kuile FO, et al. Evaluation of Plasmodium vivax malaria recurrence in Brazil. Malar J. 2019;18: 18. doi: 10.1186/s12936-019-2644-y 30670020

46. Commons RJ, Simpson JA, Thriemer K, Humphreys GS, Abreha T, Alemu SG, et al. The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis. Lancet Infect Dis. 2018;18: 1025–1034. doi: 10.1016/S1473-3099(18)30348-7 30033231

47. Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26: 589–595. doi: 10.1093/bioinformatics/btp698 20080505

48. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

49. Paradis E, Claude J, Strimmer K. APE: Analyses of Phylogenetics and Evolution in R language. Bioinformatics. 2004;20: 289–290. doi: 10.1093/bioinformatics/btg412 14734327

50. Stekhoven DJ, Bühlmann P. MissForest—non-parametric missing value imputation for mixed-type data. Bioinformatics. 2012;28: 112–118. Available: http://dx.doi.org/10.1093/bioinformatics/btr597 22039212

51. Breiman L. Random Forests. Mach Learn. 2001;45: 5–32. doi: 10.1023/A:1010933404324

52. Mangin B, Siberchicot A, Nicolas S, Doligez A, This P, Cierco-Ayrolles C. Novel measures of linkage disequilibrium that correct the bias due to population structure and relatedness. Heredity (Edinb). 2012;108: 285–291. doi: 10.1038/hdy.2011.73 21878986

53. Benavente ED, Oresegun DR, de Sessions PF, Walker EM, Roper C, Dombrowski JG, et al. Global genetic diversity of var2csa in Plasmodium falciparum with implications for malaria in pregnancy and vaccine development. Sci Rep. 2018;8: 15429. doi: 10.1038/s41598-018-33767-3 30337594

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se