Chapter 16 : Genome Diversity, Population Genetics, and Evolution of Malaria Parasites

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Genome Diversity, Population Genetics, and Evolution of Malaria Parasites, Page 1 of 2

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Malaria parasites infect an impressively broad range of vertebrate hosts, with over 100 species identified in mammals, reptiles, and birds. The majority of malaria parasites are transmitted by mosquitoes; human malaria parasites are transmitted by anopheline mosquitoes exclusively. The study of genome diversity and plasticity, particularly at chromosome ends, is a robust area of research within the malaria community. A class of polymorphisms contributing to genome diversity and plasticity is deletions and insertions (indels) of short repetitive DNA sequences, known as microsatellites (MS) or minisatellites depending on the size of the repeated unit. Gene copy number variation (CNV) is yet another factor contributing to genome diversity in malaria parasites. In CNV has been detected for many genes by using high-density microarray and/or real-time PCR. Malaria parasites have relatively high recombination rates compared with other organisms studied, such as humans and mice. The degree and extent of genome diversity is tightly linked to parasite origins and evolutionary history. Genome-wide polymorphic single nucleotide polymorphisms (SNPs) can be applied to mapping genes or mutations that are associated with parasite phenotypes of interest. The genome is at least as diverse as that of , according to estimates of the nucleotide substitution rate. An understanding of the genome diversity of malaria parasites provides valuable insights into parasite evolution, population structure, dynamics of transmission, mechanisms of drug resistance, immune evasion, and parasite development.

Citation: Su X, Joy D. 2012. Genome Diversity, Population Genetics, and Evolution of Malaria Parasites, p 269-285. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch16

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Restriction Fragment Length Polymorphism
Merozoite Surface Protein 1
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Cartoon of the life cycle, showing stages of DNA replication and genetic recombination. doi:10.1128/9781555817213.ch16f01

Citation: Su X, Joy D. 2012. Genome Diversity, Population Genetics, and Evolution of Malaria Parasites, p 269-285. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch16
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Diversity generation, types of polymorphism, effects of genetic variation, and potential applications. doi:10.1128/9781555817213.ch16f02

Citation: Su X, Joy D. 2012. Genome Diversity, Population Genetics, and Evolution of Malaria Parasites, p 269-285. In Hacker J, Dobrindt U, Kurth R (ed), Genome Plasticity and Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/9781555817213.ch16
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1. Absalan, F.,, and M. Ronaghi. 2007. Molecular inversion probe assay. Methods Mol. Biol. 396:315330.
2. Anderson, T. J., 2004. Mapping drug resistance genes in Plasmodium falciparum by genome-wide association. Curr. Drug Targets Infect. Disord. 4:6578.
3. Anderson, T. J.,, and K. P. Day. 2000. Geographical structure and sequence evolution as inferred from the Plasmodium falciparum S-antigen locus. Mol. Biochem. Parasitol. 106:321326.
4. Anderson, T. J.,, B. Haubold,, J. T. Williams,, J. G. Estrada-Franco,, L. Richardson,, R. Mollinedo,, M. Bockarie,, J. Mokili,, S. Mharakurwa,, N. French,, J. Whitworth,, I. D. Velez,, A. H. Brockman,, F. Nosten,, M. U. Ferreira,, and K. P. Day. 2000. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol. Biol. Evol. 17:14671482.
5. Baruch, D. I.,, B. L. Pasloske,, H. B. Singh,, X. Bi,, X. C. Ma,, M. Feldman,, T. F. Taraschi,, and R. J. Howard. 1995. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82:7787.
6. Bennett, S. T.,, C. Barnes,, A. Cox,, L. Davies,, and C. Brown. 2005. Toward the 1,000 dollars human genome. Pharmacogenomics 6:373382.
7. Biggs, B. A.,, D. J. Kemp,, and G. V. Brown. 1989. Subtelomeric chromosome deletions in field isolates of Plasmodium falciparum and their relationship to loss of cytoadherence in vitro. Proc. Natl. Acad. Sci. USA 86:24282432.
8. Bottius, E.,, N. Bakhsis,, and A. Scherf. 1998. Plasmodium falciparum telomerase: de novo telomere addition to telomeric and nontelomeric sequences and role in chromosome healing. Mol. Cell. Biol. 18: 919925.
9. Bozdech, Z.,, S. Mok,, G. Hu,, M. Imwong,, A. Jaidee,, B. Russell,, H. Ginsburg,, F. Nosten,, N. P. Day,, N. J. White,, J. M. Carlton,, and P. R. Preiser. 2008. The transcriptome of Plasmodium vivax reveals divergence and diversity of transcriptional regulation in malaria parasites. Proc. Natl. Acad. Sci. USA 105:1629016295.
10. Carlton, J. 2003. The Plasmodium vivax genome sequencing project. Trends Parasitol. 19:227231.
11. Carlton, J. M.,, J. H. Adams,, J. C. Silva,, S. L. Bidwell,, H. Lorenzi,, E. Caler,, J. Crabtree,, S. V. Angiuoli,, E. F. Merino,, P. Amedeo,, Q. Cheng,, R. M. Coulson,, B. S. Crabb,, H. A. Del Portillo,, K. Essien,, T. V. Feldblyum,, C. Fernandez-Becerra,, P. R. Gilson,, A. H. Gueye,, X. Guo,, S. Kang’a,, T. W. Kooij,, M. Korsinczky,, E. V. Meyer,, V. Nene,, I. Paulsen,, O. White,, S. A. Ralph,, Q. Ren,, T. J. Sargeant,, S. L. Salzberg,, C. J. Stoeckert,, S. A. Sullivan,, M. M. Yamamoto,, S. L. Hoffman,, J. R. Wortman,, M. J. Gardner,, M. R. Galinski,, J. W. Barnwell,, and C. M. Fraser-Liggett. 2008. Comparative genomics of the neglected human malaria parasite Plasmodium vivax. Nature 455:757763.
12. Carlton, J. M.,, S. V. Angiuoli,, B. B. Suh,, T. W. Kooij,, M. Pertea,, J. C. Silva,, M. D. Ermolaeva,, J. E. Allen,, J. D. Selengut,, H. L. Koo,, J. D. Peterson,, M. Pop,, D. S. Kosack,, M. F. Shumway,, S. L. Bidwell,, S. J. Shallom,, S. E. van Aken,, S. B. Riedmuller,, T. V. Feldblyum,, J. K. Cho,, J. Quackenbush,, M. Sedegah,, A. Shoaibi,, L. M. Cummings,, L. Florens,, J. R. Yates,, J. D. Raine,, R. E. Sinden,, M. A. Harris,, D. A. Cunningham,, P. R. Preiser,, L. W. Bergman,, A. B. Vaidya,, L. H. van Lin,, C. J. Janse,, A. P. Waters,, H. O. Smith,, O R. White,, S. L. Salzberg,, J. C. Venter,, C. M. Fraser,, S. L. Hoffman,, M. J. Gardner,, and D. J. Carucci. 2002. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature 419:512519.
13. Carlton, J.,, J. Silva,, and N. Hall. 2005. The genome of model malaria parasites, and comparative genomics. Curr. Issues Mol. Biol. 7:2337.
14. Carlton, J. M.,, R. Vinkenoog,, A. P. Waters,, and D. Walliker. 1998. Gene synteny in species of Plasmodium. Mol. Biochem. Parasitol. 93:285294.
15. Carter, R.,, and K. N. Mendis. 2002. Evolutionary and historical aspects of the burden of malaria. Clin. Microbiol. Rev. 15:564594.
16. Carter, R.,, and A. Voller. 1975. The distribution of enzyme variation in populations of Plasmodium falciparum in Africa. Trans. R. Soc. Trop. Med. Hyg. 69:371376.
17. Chen, Q.,, V. Fernandez,, A. Sundstrom,, M. Schlichtherle,, S. Datta,, P. Hagblom,, and M. Wahlgren. 1998. Developmental selection of var gene expression in Plasmodium falciparum. Nature 394:392395.
18. Coluzzi, M. 1999. The clay feet of the malaria giant and its African roots: hypotheses and inferences about origin, spread and control of Plasmodium falciparum. Parassitologia 41:277283.
19. Coluzzi, M.,, A. Sabatini,, A. della Torre,, M. A. di Deco,, and V. Petrarca. 2002. A polytene chromosome analysis of the Anopheles gambiae species complex. Science 298:14151418.
20. Conway, D. J.,, C. Fanello,, J. M. Lloyd,, B. M. al-Joubori,, A. H. Baloch,, S. D. Somanath,, C. Roper,, A. M. Oduola,, B. Mulder,, M. M. Povoa,, B. Singh,, and A. W. Thomas. 2000. Origin of Plasmodium falciparum malaria is traced by mitochondrial DNA. Mol. Biochem. Parasitol. 111: 163171.
21. Conway, D. J.,, C. Roper,, A. M. Oduola,, D. E. Arnot,, P. G. Kremsner,, M. P. Grobusch,, C. F. Curtis,, and B. M. Greenwood. 1999. High recombination rate in natural populations of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 96:45064511.
22. Cornejo, O. E.,, and A. A. Escalante. 2006. The origin and age of Plasmodium vivax. Trends Parasitol. 22:558563.
23. Cortes, A.,, M. Mellombo,, R. Masciantonio,, V. J. Murphy,, J. C. Reeder,, and R. F. Anders. 2005. Allele specificity of naturally acquired antibody responses against Plasmodium falciparum apical membrane antigen 1. Infect. Immun. 73:422430.
24. Cowman, A. F.,, D. Galatis,, and J. K. Thompson. 1994. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc. Natl. Acad. Sci. USA 91:11431147.
25. Cunningham, D.,, J. Fonager,, W. Jarra,, C. Carret,, P. Preiser,, and J. Langhorne. 2009. Rapid changes in transcription profiles of the Plasmodium yoelii yir multigene family in clonal populations: lack of epigenetic memory? PLoS One 4:e4285.
26. Day, K .P.,, F. Karamalis,, J. Thompson,, D. A. Barnes,, C. Peterson,, H. Brown,, G. V. Brown,, and D. J. Kemp. 1993. Genes necessary for expression of a virulence determinant and for transmission of Plasmodium falciparum are located on a 0.3-megabase region of chromosome 9. Proc. Natl. Acad. Sci. USA 90:82928296.
27. Day, K. P.,, J. C. Koella,, S. Nee,, S. Gupta,, and A. F. Read. 1992. Population genetics and dynamics of Plasmodium falciparum: an ecological view. Parasitology 104:S3552.
28. Deitsch, K. W.,, A. del Pinal,, and T. E. Wellems. 1999. Intra-cluster recombination and var transcription switches in the antigenic variation of Plasmodium falciparum. Mol. Biochem. Parasitol. 101:107116.
29. del Portillo, H. A.,, M. Lanzer,, S. Rodriguez-Malaga,, F. Zavala,, and C. Fernandez-Becerra. 2004. Variant genes and the spleen in Plasmodium vivax malaria. Int. J. Parasitol. 34:15471554.
30. Dharia, N. V.,, A. B. Sidhu,, M. B. Cassera,, S. J. Westenberger,, S. E. Bopp,, R. T. Eastman,, D. Plouffe,, S. Batalov,, D. J. Park,, S. K. Volkman,, D. F. Wirth,, Y. Zhou,, D. A. Fidock,, and E. A. Winzeler. 2009. Use of high-density tiling microarrays to identify mutations globally and elucidate mechanisms of drug resistance in Plasmodium falciparum. Genome Biol. 10:R21.
31. Duan, J.,, J. Mu,, M. A. Thera,, D. Joy,, S. L. Kosakovsky Pond,, D. Diemert,, C. Long,, H. Zhou,, K. Miura,, A. Ouattara,, A. Dolo,, O. Doumbo,, X. Z. Su,, and L. Miller. 2008. Population structure of the genes encoding the polymorphic Plasmodium falciparum apical membrane antigen 1: implications for vaccine design. Proc. Natl. Acad. Sci. USA 105:78577862.
32. Feng, X.,, J. M. Carlton,, D. A. Joy,, J. Mu,, T. Furuya,, B. B. Suh,, Y. Wang,, J. W. Barnwell,, and X. Z. Su. 2003. Single-nucleotide polymorphisms and genome diversity in Plasmodium vivax. Proc. Natl. Acad. Sci. USA 100:85028507.
33. Ferdig, M. T.,, and X.-Z. Su. 2000. Microsatellite markers and genetic mapping in Plasmodium falciparum. Parasitol. Today 7:307312.
34. Ferreira, M. U.,, N. D. Karunaweera,, M. da Silva-Nunes,, N. S. da Silva,, D. F. Wirth,, and D. L. Hartl. 2007. Population structure and transmission dynamics of Plasmodium vivax in rural Amazonia. J. Infect. Dis. 195:12181226.
35. Figtree, M.,, C. J. Pasay,, R. Slade,, Q. Cheng,, N. Cloonan,, J. Walker,, and A. Saul. 2000. Plasmodium vivax synonymous substitution frequencies, evolution and population structure deduced from diversity in AMA 1 and MSP 1 genes. Mol. Biochem. Parasitol. 108:5366.
36. Freitas-Junior, L. H.,, E. Bottius,, L. A. Pirrit,, K. W. Deitsch,, C. Scheidig,, F. Guinet,, U. Nehrbass,, T. E. Wellems,, and A. Scherf. 2000. Frequent ectopic recombination of virulence factor genes in telomeric chromosome clusters of P. falciparum. Nature 407:10181022.
37. Gardner, M. J.,, N. Hall,, E. Fung,, O. White,, M. Berriman,, R. W. Hyman,, J. M. Carlton,, A. Pain,, K. E. Nelson,, S. Bowman,, I. T. Paulsen,, K. James,, J. A. Eisen,, K. Rutherford,, S. L. Salzberg,, A. Craig,, S. Kyes,, M. S. Chan,, V. Nene,, S. J. Shallom,, B. Suh,, J. Peterson,, S. Angiuoli,, M. Pertea,, J. Allen,, J. Selengut,, D. Haft,, M. W. Mather,, A. B. Vaidya,, D. M. Martin,, A. H. Fairlamb,, M. J. Fraunholz,, D. S. Roos,, S. A. Ralph,, G. I. McFadden,, L. M. Cummings,, G. M. Subramanian,, C. Mungall,, J. C. Venter,, D. J. Carucci,, S. L. Hoffman,, C. Newbold,, R. W. Davis,, C. M. Fraser,, and B. Barrell. 2002. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498511.
38. Gonzalez-Ceron, L.,, M. H. Rodriguez,, F. V. Santillan,, J. E. Hernandez,, and R. A. Wirtz. 2000. Susceptibility of three laboratory strains of Anopheles albimanus (Diptera: Culicidae) to coindigenous Plasmodium vivax circumsporozoite protein phenotypes in southern Mexico. J. Med. Entomol. 37:331334.
39. Grech, K.,, A. Martinelli,, S. Pathirana,, D. Walliker,, P. Hunt,, and R. Carter. 2002. Numerous, robust genetic markers for Plasmodium chabaudi by the method of amplified fragment length polymorphism. Mol. Biochem. Parasitol. 123:95104.
40. Hall, N.,, M. Karras,, J. D. Raine,, J. M. Carlton,, T. W. Kooij,, M. Berriman,, L. Florens,, C. S. Janssen,, A. Pain,, G. K. Christophides,, K. James,, K. Rutherford,, B. Harris,, D. Harris,, C. Churcher,, M. A. Quail,, D. Ormond,, J. Doggett,, H, E. Trueman,, J. Mendoza,, S. L. Bidwell,, M. A. Rajandream,, D. J. Carucci,, J. R. Yates III,, F. C. Kafatos,, C. J. Janse,, B. Barrell,, C. M. Turner,, A. P. Waters,, and R. E. Sinden. 2005. A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses. Science 307:8286.
41. Hardenbol, P.,, J. Baner,, M. Jain,, M. Nilsson,, E. A. Namsaraev,, G. A. Karlin-Neumann,, H. Fakhrai-Rad,, M. Ronaghi,, T. D. Willis,, U. Landegren,, and R. W. Davis. 2003. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 21:673678.
42. Hayton, K.,, D. Gaur,, A. Liu,, J. Takahashi,, B. Henschen,, S. Singh,, L. Lambert,, T. Furuya,, R. Bouttenot,, M. Doll,, F. Nawaz,, J. Mu,, L. Jiang,, L. H. Miller,, and T. E. Wellems. 2008. Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion. Cell Host Microbe 4:4051.
43. Hayton, K.,, and X.-Z. Su. 2004. Genetic and biochemical aspects of drug resistance in malaria parasites. Curr. Drug Targets Infect. Disord. 4:110.
44. Hey, J. 1999. Parasite populations: the puzzle of Plasmodium. Curr. Biol. 9:R565567.
45. Howard, R. J.,, J. W. Barnwell,, E. P. Rock,, J. Neequaye,, D. Ofori-Adjei,, W. L. Maloy,, J. A. Lyon,, and A. Saul. 1988. Two approximately 300 kilodalton Plasmodium falciparum proteins at the surface membrane of infected erythrocytes. Mol. Biochem. Parasitol. 27:207223.
46. Hughes, A. L. 2004. The evolution of amino acid repeat arrays in Plasmodium and other organisms. J. Mol. Evol. 59:528535.
47. Hughes, A. L.,, and F. Verra. 2002. Extensive polymorphism and ancient origin of Plasmodium falciparum. Trends Parasitol. 18:348351.
48. Imwong, M.,, S. Nair,, S. Pukrittayakamee,, D. Sudimack,, J. T. Williams,, M. Mayxay,, P. N. Newton,, J. R. Kim,, A. Nandy,, L. Osorio,, J. M. Carlton,, N. J. White,, N. P. Day,, and T. J. Anderson. 2007. Contrasting genetic structure in Plasmodium vivax populations from Asia and South America. Int. J. Parasitol. 37:10131022.
49. Imwong, M.,, D. Sudimack,, S. Pukrittayakamee,, L. Osorio,, J. M. Carlton,, N. P. Day,, N. J. White,, and T. J. Anderson. 2006. Microsatellite variation, repeat array length, and population history of Plasmodium vivax. Mol. Biol. Evol. 23:10161018.
50. Janse, C. J.,, J. M. Carlton,, D. Walliker,, and A. P. Waters. 1994. Conserved location of genes on polymorphic chromosomes of four species of malaria parasites. Mol. Biochem. Parasitol. 68:285296.
51. Janse, C. J.,, and A. P. Waters. 1993. Genome organization, chromosome translocation and size polymorphism in rodent malaria parasites. Parassitologia 35(Suppl.):5153.
52. Janssen, C. S.,, M. P. Barrett,, C. M. Turner,, and R. S. Phillips. 2002. A large gene family for putative variant antigens shared by human and rodent malaria parasites. Proc. Biol. Sci. 269:431436.
53. Jeffares, D. C.,, A. Pain,, A. Berry,, A. V. Cox,, J. Stalker,, C. E. Ingle,, A. Thomas,, M. A. Quail,, K. Siebenthall,, A. C. Uhlemann,, S. Kyes,, S. Krishna,, C. Newbold,, E. T. Dermitzakis,, and M. Berriman. 2007. Genome variation and evolution of the malaria parasite Plasmodium falciparum. Nat. Genet. 39:120125.
54. Jiang, H.,, J. J. Patel,, M. Yi,, J. Mu,, J. Ding,, R. Stephens,, R. A. Cooper,, M. T. Ferdig,, and X.-Z. Su. 2008a. Genome-wide compensatory changes accompany drug-selected mutations in the Plasmodium falciparum crt gene. PLoS One 3:e2484.
55. Jiang, H.,, M. Yi,, J. Mu,, L. Zhang,, A. Ivens,, L. J. Klimczak,, Y. Huyen,, R. M. Stephens,, and X. -Z Su. 2008b. Detection of genome wide polymorphisms in the AT rich Plasmodium falciparum genome using a high density microarray. BMC Genomics 9:398.
56. Johnson, D. J.,, D. A. Fidock,, M. Mungthin,, V. Lakshmanan,, A. B. Sidhu,, P. G. Bray,, and S. A. Ward. 2004. Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents. Mol. Cell 15:867877.
57. Jongwutiwes, S.,, C. Putaporntip,, T. Iwasaki,, M. U. Ferreira,, H. Kanbara,, and A. L. Hughes. 2005. Mitochondrial genome sequences support ancient population expansion in Plasmodium vivax. Mol. Biol. Evol. 22:17331739.
58. Joy, D. A.,, X. Feng,, J. Mu,, T. Furuya,, K. Chotivanich,, A. U. Krettli,, M. Ho,, A. Wang,, N. J. White,, E. Suh,, P. Beerli,, and X.-Z. Su. 2003. Early origin and recent expansion of Plasmodium falciparum. Science 300:318321.
59. Joy, D. A.,, L. Gonzalez-Ceron,, J. M. Carlton,, A. Gueye,, M. Fay,, T. F. McCutchan,, and X. -Z Su. 2008. Local adaptation and vector-mediated population structure in Plasmodium vivax malaria. Mol. Biol. Evol. 25:12451252.
60. Joy, D. A.,, J. Mu,, H. Jiang,, and X.-Z. Su. 2006. Genetic diversity and population history of Plasmodium falciparum and Plasmodium vivax. Parassitologia 48:561566.
61. Karunaweera, N. D.,, M. U. Ferreira,, A. Munasinghe,, J. W. Barnwell,, W. E. Collins,, C. L. King,, F. Kawamoto,, D. L. Hartl,, and D. F. Wirth. 2008. Extensive microsatellite diversity in the human malaria parasite Plasmodium vivax. Gene 410:105112.
62. Kemp, D. J.,, L. M. Corcoran,, R. L. Coppel,, H. D. Stahl,, A. E. Bianco,, G. V. Brown,, and R. F. Anders. 1985. Size variation in chromosomes from independent cultured isolates of Plasmodium falciparum. Nature 315:347350.
63. Kemp, D. J.,, A. F. Cowman,, and D. Walliker. 1990. Genetic diversity in Plasmodium falciparum. Adv. Parasitol. 29:75149.
64. Kemp, D. J.,, J. Thompson,, D. A. Barnes,, T. Triglia,, F. Karamalis,, C. Petersen,, G. V. Brown,, and K. P. Day. 1992. A chromosome 9 deletion in Plasmodium falciparum results in loss of cytoadherence. Mem. Inst. Oswaldo Cruz 87:8589.
65. Kidgell, C.,, S. K. Volkman,, J. Daily,, J. O. Borevitz,, D. Plouffe,, Y. Zhou,, J. R. Johnson,, K. Le Roch,, O. Sarr,, O. Ndir,, S. Mboup,, S. Batalov,, D. F. Wirth,, and E. A. Winzeler. 2006. A systematic map of genetic variation in Plasmodium falciparum. PLoS Pathog. 2:e57.
66. Kooij, T. W.,, J. M. Carlton,, S. L. Bidwell,, N. Hall,, J. Ramesar,, C. J. Janse,, and A. P. Waters. 2005. A Plasmodium whole-genome synteny map: indels and synteny breakpoints as foci for species-specific genes. PLoS Pathog. 1:e44.
67. Kroutil, L. C.,, and T. A. Kunkel. 1999. Deletion errors generated during replication of CAG repeats. Nucleic Acids Res. 27:34813486.
68. Langsley, G.,, J. Patarapotikul,, S. Handunnetti,, E. Khouri,, K. N. Mendis,, and P. H. David. 1988. Plasmodium vivax: karyotype polymorphism of field isolates. Exp. Parasitol. 67:301306.
69. Lanzer, M.,, K. Fischer,, and S. M. Le Blancq. 1995. Parasitism and chromosome dynamics in protozoan parasites: is there a connection? Mol. Biochem. Parasitol. 70:18.
70. Leclerc, M. C.,, P. Durand,, C. Gauthier,, S. Patot,, N. Billotte,, M. Menegon,, C. Severini,, F. J. Ayala,, and F. Renaud. 2004. Meager genetic variability of the human malaria agent Plasmodium vivax. Proc. Natl. Acad. Sci. USA 101:1445514460.
71. Li, J.,, W. E. Collins,, R. A. Wirtz,, D. Rathore,, A. Lal,, and T. F. McCutchan. 2001. Geographic subdivision of the range of the malaria parasite Plasmodium vivax. Emerg. Infect. Dis. 7:3542.
72. Li, J.,, Y. Zhang,, S. Liu,, L. Hong,, M. Sullivan,, T. F. McCutchan,, J. M. Carlton,, and X. Z. Su. 2009. Hundreds of microsatellites for genotyping Plasmodium yoelii parasites. Mol. Biochem. Parasitol. 166:153158.
73. Li, J.,, Y. Zhang,, M. Sullivan,, L. Hong,, L. Huang,, F. Lu,, T. F. McCutchan,, and X. Z. Su. 2007. Typing Plasmodium yoelii microsatellites using a simple and affordable fluorescent labeling method. Mol. Biochem. Parasitol. 155:94102.
74. Lu, F.,, H. Jiang,, J. Ding,, J. Mu,, J. G. Valenzuela,, J. M. Ribeiro,, and X. Z. Su. 2007. cDNA sequences reveal considerable gene prediction inaccuracy in the Plasmodium falciparum genome. BMC Genomics 8:255.
75. Martinelli, A.,, P. Hunt,, R. Fawcett,, P. V. Cravo,, D. Walliker,, and R. Carter. 2005. An AFLP-based genetic linkage map of Plasmodium chabaudi chabaudi. Malar. J. 4:11.
76. McCollum, A. M.,, K. Mueller,, L. Villegas,, V. Udhayakumar,, and A. A. Escalante. 2007. Common origin and fixation of Plasmodium falciparum dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance in a low-transmission area in South America. Antimicrob. Agents Chemother. 51:20852091.
77. Mu, J.,, P. Awadalla,, J. Duan,, K. M. McGee,, D. A. Joy,, G. A. McVean,, and X.-Z. Su. 2005a. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol. 3:e335.
78. Mu, J.,, P. Awadalla,, J. Duan,, K. M. McGee,, J. Keebler,, K. Seydel,, G. A. McVean,, and X.-Z. Su. 2007. Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nat. Genet. 39:126130.
79. Mu, J.,, J. Duan,, K. Makova,, D. A. Joy,, C. Q. Huynh,, O. H. Branch,, W.-H. Li,, and X. -Z Su. 2002. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418:323326.
80. Mu, J.,, R. A. Myers,, H. Jiang,, S. Liu,, S. Ricklefs,, M. Waisberg,, K. Chotivanich,, P. Wilairatana,, S. Krudsood,, N. J. White,, R. Udomsangpetch,, L. Cui,, M. Ho,., F. Ou,, H. Li,, J. Song,, G. Li,, X. Wang,, S. Seila,, S. Sokunthea,, D. Socheat,, D. E. Sturdevant,, S. F. Porcella,, R. M. Fairhurst,, T. E. Wellems,, P. Awadalla,, and S.-Z. Su. 2010. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat. Genet. 42:268271.
81. Mu, J.,, D. A. Joy,, J. Duan,, Y. Huang,, J. Carlton,, J. Walker,, J. Barnwell,, P. Beerli,, M. A. Charleston,, O. G. Pybus,, and X.-Z. Su. 2005b. Host switch leads to emergence of Plasmodium vivax malaria in humans. Mol. Biol. Evol. 22:16861693.
82. Na-Bangchang, K.,, and K. Congpuong. 2007. Current malaria status and distribution of drug resistance in east and southeast Asia with special focus to Thailand. Tohoku J. Exp. Med. 211:99113.
83. Nair, S.,, B. Miller,, M. Barends,, A. Jaidee,, J. Patel,, M. Mayxay,, P. Newton,, F. Nosten,, M. T. Ferdig,, and T. J. Anderson. 2008. Adaptive copy number evolution in malaria parasites. PLoS Genet. 4:e1000243.
84. Nair, S.,, D. Nash,, D. Sudimack,, A. Jaidee,, M. Barends,, A. C. Uhlemann,, S. Krishna,, F. Nosten,, and T. J. Anderson. 2007. Recurrent gene amplification and soft selective sweeps during evolution of multidrug resistance in malaria parasites. Mol. Biol. Evol. 24:562573.
85. Nair, S.,, J. T. Williams,, A. Brockman,, L. Paiphun,, M. Mayxay,, P. N. Newton,, J. P. Guthmann,, F. M. Smithuis,, T. T. Hien,, N. J. White,, F. Nosten,, and T. J. Anderson. 2003. A selective sweep driven by pyrimethamine treatment in southeast Asian malaria parasites. Mol. Biol. Evol. 20:15261536.
86. Neafsey, D. E.,, S. F. Schaffner,, S. K. Volkman,, D. Park,, P. Montgomery,, D. A. Milner, Jr.,, A. Lukens,, D. Rosen,, R. Daniels,, N. Houde,, J. F. Cortese,, E. Tyndall,, C. Gates,, N. Stange-Thomann,, O. Sarr,, D. Ndiaye,, O. Ndir,, S. Mboup,, M. U. Ferreira,, S. D. Moraes,, A. P. Dash,, C. E. Chitnis,, R. C. Wiegand,, D. L. Hartl,, B. W. Birren,, E. S. Lander,, P. C. Sabeti,, and D. F. Wirth. 2008. Genome-wide SNP genotyping highlights the role of natural selection in Plasmodium falciparum population divergence. Genome Biol. 9:R171.
87. Pearce, R. J.,, H. Pota,, M. S. Evehe,, E.-H. ,, G. Mombo-Ngoma,, A. L. Malisa,, R. Ord,, W. Inojosa,, A. Matondo,, D. A. Diallo,, W. Mbacham,, I. V. van den Broek,, T. D. Swarthout,, A. Getachew,, S. Dejene,, M. P. Grobusch,, F. Njie,, S. Dunyo,, M. Kweku,, S. Owusu-Agyei,, D. Chandramohan,, M. Bonnet,, J. P. Guthmann,, S. Clarke,, K. I. Barnes,, E. Streat,, S. T. Katokele,, P. Uusiku,, C. O. Agboghoroma,, O Y, Elegba,, B. Cissé,, I. E. A-Elbasit,, H. A. Giha,, S. P. Kachur,, C. Lynch,, J. B. Rwakimari,, P. Chanda,, P., M. Hawela,, B. Sharp,, I. Naidoo,, and C. Roper. 2009. Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria. PLoS Med. 6:e1000055.
88. Polley, S. D.,, and D. J. Conway. 2001. Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene. Genetics 158:15051512.
89. Pologe, L. G.,, and J. V. Ravetch. 1986. A chromosomal rearrangement in a P. falciparum histidine-rich protein gene is associated with the knobless phenotype. Nature 322:474477.
90. Preechapornkul, P.,, M. Imwong,, K. Chotivanich,, W. Pongtavornpinyo,, A. M. Dondorp,, N. P. Day,, N. J. White,, and S. Pukrittayakamee. 2009. Plasmodium falciparum pfmdr1 amplification, mefloquine resistance, and parasite fitness. Antimicrob. Agents Chemother. 53:15091515.
91. Price, R. N.,, A. C. Uhlemann,, A. Brockman,, R. McGready,, E. Ashley,, L. Phaipun,, R. Patel,, K. Laing,, S. Looareesuwan,, N. J. White,, F. Nosten,, and S. Krishna. 2004. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet 364:438447.
92. Putaporntip, C.,, S. Jongwutiwes,, and A. L. Hughes. 2009. Natural selection maintains a stable polymorphism at the circumsporozoite protein locus of Plasmodium falciparum in a low endemic area. Infect. Genet. Evol. 9:567573.
93. Raj, D. K.,, J. Mu,, H. Jiang,, J. Kabat,, S. Singh,, M. Sullivan,, M. P. Fay,, T. F. McCutchan,, and X. Z. Su. 2008. Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. J. Biol. Chem. 284:76877696.
94. Rathod, P. K.,, T. McErlean,, and P. C. Lee. 1997. Variations in frequencies of drug resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 94:93899393.
95. Razakandrainibe, F. G.,, P. Durand,, J. C. Koella,, T. De Meeus,, F. Rousset,, F. J. Ayala,, and F. Renaud. 2005. “Clonal” population structure of the malaria agent Plasmodium falciparum in high-infection regions. Proc. Natl. Acad. Sci. USA 102:1738817393.
96. Reed, F. A.,, and S. A. Tishkoff. 2006. Positive selection can create false hotspots of recombination. Genetics 172:20112014.
97. Reed, M. B.,, K. J. Saliba,, S. R. Caruana,, K. Kirk,, and A. F. Cowman. 2000. Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 403:906909.
98. Ribacke, U.,, B. W. Mok,, V. Wirta,, J. Normark,, J. Lundeberg,, F. Kironde,, T. G. Egwang,, P. Nilsson,, and M. Wahlgren. 2007. Genome wide gene amplifications and deletions in Plasmodium falciparum. Mol. Biochem. Parasitol. 155:3344.
99. Rich, S. M.,, R. R. Hudson,, and F. J. Ayala. 1997. Plasmodium falciparum antigenic diversity: evidence of clonal population structure. Proc. Natl. Acad. Sci. USA 94:1304013045.
100. Rich, S. M.,, M. C. Licht,, R. R. Hudson,, and F. J. Ayala. 1998. Malaria’s Eve: evidence of a recent population bottleneck throughout the world populations of Plasmodium falciparum. Proc. Natl. Acad. Sci. USA 95:44254430.
101. Roper, C.,, R. Pearce,, B. Bredenkamp,, J. Gumede,, C. Drakeley,, F. Mosha,, D. Chandramohan,, and B. Sharp. 2003. Antifolate antimalarial resistance in southeast Africa: a population-based analysis. Lancet 361:11741181.
102. Roper, C.,, R. Pearce,, S. Nair,, B. Sharp,, F. Nosten,, and T. Anderson. 2004. Intercontinental spread of pyrimethamine-resistant malaria. Science 305:1124.
103. Scherf, A.,, C. Behr,, J. L. Sarthou,, M. Pla,, C. Rogier,, J. F. Trape,, L. P. da Silva,, and P. Dubois. 1993. Immune response in mouse and malaria-exposed humans to peptides derived from Pf11-1, a highly repetitive megadalton protein of Plasmodium falciparum. Eur. J. Immunol. 23:15741581.
104. Scherf, A.,, and D. Mattei. 1992. Cloning and characterization of chromosome breakpoints of Plasmodium falciparum: breakage and new telomere formation occurs frequently and randomly in subtelomeric genes. Nucleic Acids Res. 20:14911496.
105. Sidhu, A. B.,, A. C. Uhlemann,, S. G. Valderramos,, J. C. Valderramos,, S. Krishna,, and D. A. Fidock. 2006. Decreasing pfmdr1 copy number in Plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. J. Infect. Dis. 194:528535.
106. Singh, B.,, L. Kim Sung,, A. Matusop,, A. Radhakrishnan,, S. S. Shamsul,, J. Cox-Singh,, A. Thomas,, and D. J. Conway. 2004. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 363:10171024.
107. Smith, J. D.,, C. E. Chitnis,, A. G. Craig,, D. J. Roberts,, D. E. Hudson-Taylor,, D. S. Peterson,, R. Pinches,, C. I. Newbold,, and L. H. Miller. 1995. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82:101110.
108. Snow, R. W.,, C. A. Guerra,, A. M. Noor,, H. Y. Myint,, and S. I. Hay. 2005. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434:214217.
109. Su, X.-Z.,, M. T. Ferdig,, Y. Huang,, C. Q. Huynh,, A. Liu,, J. You,, J. C. Wootton,, and T. E. Wellems. 1999. A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286:13511353.
110. Su, X.-Z.,, V. M. Heatwole,, S. P. Wertheimer,, F. Guinet,, J. A. Herrfeldt,, D. S. Peterson,, J. A. Ravetch,, and T. E. Wellems. 1995. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82:89100.
111. Su, X.-Z.,, L. A. Kirkman,, H. Fujioka,, and T. E. Wellems. 1997. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in southeast Asia and Africa. Cell 91:593603.
112. Su, X.-Z.,, J. Mu,, and D. A. Joy. 2003. The “Malaria’s Eve” hypothesis and the debate concerning the origin of the human malaria parasite Plasmodium falciparum. Microbes Infect. 5:891896.
113. Su, X.-Z.,, and T. E. Wellems. 1996. Toward a high-resolution Plasmodium falciparum linkage map: polymorphic markers from hundreds of simple sequence repeats. Genomics 33:430444.
114. Su, X.-Z.,, and J. C. Wootton. 2004. Genetic mapping in the human malaria parasite Plasmodium falciparum. Mol. Microbiol. 53:15731582.
115. Tami, A.,, H. Grundmann,, C. Sutherland,, J. S. McBride,, D R. Cavanagh,, E. Campos,, G. Snounou,, C. Barnabe,, M. Tibayrenc,, and D. C. Warhurst. 2002. Restricted genetic and antigenic diversity of Plasmodium falciparum under mesoendemic transmission in the Venezuelan Amazon. Parasitology 124:569581.
116. Tan, J. C.,, J. J. Patel,, A. Tan,, J. C. Blain,, T. J. Albert,, N. F. Lobo,, and M. T. Ferdig. 2009. Optimizing comparative genomic hybridization probes for genotyping and SNP detection in Plasmodium falciparum. Genomics 93:543550.
117. Templeton, T. J. 2009. The varieties of gene amplification, diversification and hypervariability in the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol. 166:109116.
118. Tishkoff, S. A.,, R. Varkonyi,, N. Cahinhinan,, S. Abbes,, G. Argyropoulos,, G. Destro-Bisol,, A. Drousiotou,, B. Dangerfield,, G. Lefranc,, J. Loiselet,, A. Piro,, M. Stoneking,, A. Tagarelli,, G. Tagarelli,, E. H. Touma,, S. M. Williams,, and A. G. Clark. 2001. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293:455462.
119. Trimnell, A.,, S. Kraemer,, S. Mukherjee,, D. J. Phippard,, J. H. Janes,, E. Flamoe,, X.-z. Su,, P. Awadalla,, and J. D. Smith. 2006. Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Mol. Biol. Parasitol. 148:169180.
120. VanBuskirk, K. M.,, M. T. O’Neill,, P. De La Vega,, A. G. Maier,, U. Krzych,, J. Williams,, M.G. Dowler,, J. B. Sacci, Jr.,, N. Kangwanrangsan,, T. Tsuboi,, N. M. Kneteman,, D. G. Heppner, Jr.,, B. A. Murdock,, S. A. Mikolajczak,, A. S. Aly,, A. F. Cowman,, and S. H. Kappe. 2009. Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design. Proc. Natl. Acad. Sci. USA 106:1300413009.
121. Vekemans, J.,, and W. R. Ballou. 2008. Plasmodium falciparum malaria vaccines in development. Expert Rev. Vaccines 7:223240.
122. Volkman, S. K.,, A. E. Barry,, E. J. Lyons,, K. M. Nielsen,, S. M. Thomas,, M. Choi,, S. S. Thakore,, K. P. Day,, D. F. Wirth,, and D. L. Hartl. 2001. Recent origin of Plasmodium falciparum from a single progenitor. Science 293:482484.
123. Volkman, S. K.,, P. C. Sabeti,, D. DeCaprio,, D. E. Neafsey,, S. F. Schaffner,, D. A. Milner, Jr.,, J. P. Daily,, O. Sarr,, D. Ndiaye,, O. Ndir,, S. Mboup,, M. T. Duraisingh,, A. Lukens,, A. Derr,, N. Stange-Thomann,, S. Waggoner,, R. Onofrio,, L. Ziaugra,, E. Mauceli,, S. Gnerre,, D. B. Jaffe,, J. Zainoun,, R. C. Wiegand,, B. W. Birren,, D. L. Hartl,, J. E. Galagan,, E. S. Lander,, and D. F. Wirth. 2007. A genome-wide map of diversity in Plasmodium falciparum. Nat. Genet. 39: 113119.
124. Wakaguri, H.,, Y. Suzuki,, M. Sasaki,, S. Sugano,, and J. Watanabe. 2009. Inconsistencies of genome annotations in apicomplexan parasites revealed by 5′-end-one-pass and full-length sequences of oligo-capped cDNAs. BMC Genomics 10:312.
125. Walliker, D.,, H. Babiker,, and L. Ranford-Cartwright,. 1998. The genetic structure of malaria populations, p. 235253. In I. W. Sherman (ed.), Malaria: Parasite Biology, Pathogenesis, and Protection. ASM Press, Washington, DC.
126. Walther, M. 2006. Advances in vaccine development against the pre-erythrocytic stage of Plasmodium falciparum malaria. Expert Rev. Vaccines 5:8193.
127. Watanabe, J.,, M. Sasaki,, Y. Suzuki,, and S. Sugano. 2002. Analysis of transcriptomes of human malaria parasite Plasmodium falciparum using full-length enriched library: identification of novel genes and diverse transcription start sites of messenger RNAs. Gene 291:105113.
128. Wellems, T.,, A. M. J. Oduola,, B. Fenton,, R. Desjardins,, L. J. Panton,, and V. E. do Rosario. 1988. Chromosome size variation occurs in cloned Plasmodium falciparum on in vitro cultivation. Rev. Bras. Genet. 11:813825.
129. Wellems, T. E.,, L. J. Panton,, I. Y. Gluzman,, V. E. do Rosario,, R. W. Gwadz,, A. Walker-Jonah,, and D. J. Krogstad. 1990. Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross. Nature 345:253255.
130. Wootton, J. C.,, X. Feng,, M. T. Ferdig,, R. A. Cooper,, J. Mu,, D. I. Baruch,, A. J. Magill,, and X.-Z. Su. 2002. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418:320323.
131. World Health Organization. 2008. World Malaria Report 2008. World Health Organization, Geneva, Switzerland.
132. Yuan, J.,, R. L. Johnson,, R. Huang,, J. Wichterman,, H, Jiang,, K. Hayton,, D. A. Fidock,, T. E. Wellems,, J. Inglese,, C. P. Austin,, and X. Z. Su. 2009. Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum. Nat. Chem. Biol. 5:765771.

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