Volume 77, Issue 6_Suppl
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Malaria has been the greatest scourge of humankind for many millennia, and as a consequence has had more impact than any other pathogen in shaping the human genome. The sequencing of the human genome provides a new opportunity to determine the genetic traits that confer resistance to infection or disease. The identification of these traits can reveal immune responses, or host–parasite interactions, which may be useful for designing vaccines or new drugs. Similarly, the parasite genome sequence is being exploited to accelerate the development of new antimalarial interventions, for example by identifying parasite metabolic pathways that may be targeted by drugs. The malaria parasites are well known for their ability to undergo antigenic variation, and in parallel to cause a diverse array of disease syndromes, including the severe syndromes that commonly cause death. Genome-based technologies are being harnessed to relate gene and protein expression levels, or genetic variation, to the parasite forms that are targets of protective immunity. Well-conducted clinical studies are required to relate host or parasite diversity with disease. However, genomics studies of human populations raise important ethical issues, such as the disposition of data related to disease susceptibility or paternity, and the ability of communities to understand the nature of the research.


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  1. Fried M, Duffy PE, 1996. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272 : 1502–1504.
  2. Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, Hviid L, Theander TG, 2003. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol 49 : 179–191.
  3. Kwiatkowski DP, 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77 : 171–192.
  4. Haldane J, 1948. The rate of mutation of human genes. Hereditas 35 : 267–273.
  5. Nagel RL, Roth EF Jr, 1989. Malaria and red cell genetic defects. Blood 74 : 1213–1221.
  6. Kemp DJ, Cowman AF, Walliker D, 1990. Genetic diversity in Plasmodium falciparum. Adv Parasitol 29 : 75–149.
  7. Bull PC, Pain A, Ndungu FM, Kinyanjui SM, Roberts DJ, Newbold CI, Marsh K, 2005. Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity. J Infect Dis 192 : 1119–1126.
  8. Ntoumi F, Flori L, Mayengue PI, Matondo Maya DW, Issifou S, Deloron P, Lell B, Kremsner PG, Rihet P, 2005. Influence of carriage of hemoglobin AS and the Fc gamma receptor IIa-R131 allele on levels of immunoglobulin G2 antibodies to Plasmodium falciparum merozoite antigens in Gabonese children. J Infect Dis 192 : 1975–1980.
  9. Takala SL, Escalante AA, Branch OH, Kariuki S, Biswas S, Chaiyaroj SC, Lal AA, 2006. Genetic diversity in the Block 2 region of the merozoite surface protein 1 (MSP-1) of Plasmodium falciparum: additional complexity and selection and convergence in fragment size polymorphism. Infect Genet Evol 6 : 417–424.
  10. Miller LH, Good MF, Milon G, 1994. Malaria pathogenesis. Science 264 : 1878–1883.
  11. Yuthavong Y, Wilairat P, 1993. Protection against malaria by thalassaemia and haemoglobin variants. Parasitol Today 9 : 241–245.
  12. Weatherall DJ, Miller LH, Baruch DI, Marsh K, Doumbo OK, Casals-Pascual C, Roberts DJ, 2002. Malaria and the red cell. Hematology (Am Soc Hematol Educ Program) : 35–57.
  13. Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM, 1991. Common west African HLA antigens are associated with protection from severe malaria. Nature 352 : 595–600.
  14. Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schroder NW, Bienzle U, Schumann RR, 2006. Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci USA 103 : 177–182.
  15. Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B, 2002. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419 : 498–511.
  16. Lasonder E, Ishihama Y, Andersen JS, Vermunt AM, Pain A, Sauerwein RW, Eling WM, Hall N, Waters AP, Stunnenberg HG, Mann M, 2002. Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry. Nature 419 : 537–542.
  17. Heppner DG Jr, Kester KE, Ockenhouse CF, Tornieporth N, Ofori O, Lyon JA, Stewart VA, Dubois P, Lanar DE, Krzych U, Moris P, Angov E, Cummings JF, Leach A, Hall BT, Dutta S, Schwenk R, Hillier C, Barbosa A, Ware LA, Nair L, Darko CA, Withers MR, Ogutu B, Polhemus ME, Fukuda M, Pichyangkul S, Gettyacamin M, Diggs C, Soisson L, Milman J, Dubois MC, Garcon N, Tucker K, Wittes J, Plowe CV, Thera MA, Duombo OK, Pau MG, Goudsmit J, Ballou WR, Cohen J, 2005. Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research. Vaccine 23 : 2243–2250.
  18. Jambou R, Legrand E, Niang M, Khim N, Lim P, Volney B, Ekala MT, Bouchier C, Esterre P, Fandeur T, Mercereau-Puijalon O, 2005. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 366 : 1960–1963.
  19. Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Turbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E, 1999. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285 : 1573–1576.
  20. Mueller AK, Labaied M, Kappe SH, Matuschewski K, 2005. Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature 433 : 164–167.
  21. Clyde DF, Most H, McCarthy VC, Vanderberg JP, 1973. Immunization of man against sporozite-induced falciparum malaria. Am J Med Sci 266 : 169–177.
  22. Herrington D, Davis J, Nardin E, Beier M, Cortese J, Eddy H, Losonsky G, Hollingdale M, Sztein M, Levine M, Nussenzweig RS, Clyde D, Edelman R, 1991. Successful immunization of humans with irradiated malaria sporozoites: humoral and cellular responses of the protected individuals. Am J Trop Med Hyg 45 : 539–547.
  23. Nussenzweig RS, Vanderberg J, Most H, Orton C, 1967. Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei. Nature 216 : 160–162.
  24. Cohen S, McGregor IA, Carrington S, 1961. Gamma-globulin and acquired immunity to human malaria. Nature 192 : 733–737.
  25. McGregor IA, Carrington SP, 1963. Treatment of East African P. falciparum malaria with west African human γ-globulin. Trans R Soc Trop Med Hyg 57 : 170–175.
  26. Hughes MJ, Moore JC, Lane JD, Wilson R, Pribul PK, Younes ZN, Dobson RJ, Everest P, Reason AJ, Redfern JM, Greer FM, Paxton T, Panico M, Morris HR, Feldman RG, Santangelo JD, 2002. Identification of major outer surface proteins of Streptococcus agalactiae. Infect Immun 70 : 1254–1259.
  27. Larsson T, Bergstrom J, Nilsson C, Karlsson KA, 2000. Use of an affinity proteomics approach for the identification of low-abundant bacterial adhesins as applied on the Lewis(b)-binding adhesin of Helicobacter pylori. FEBS Lett 469 : 155–158.
  28. Fried M, Wendler JP, Mutabingwa TK, Duffy PE, 2004. Mass spectrometric analysis of Plasmodium falciparum erythrocyte membrane protein-1 variants expressed by placental malaria parasites. Proteomics 4 : 1086–1093.
  29. Le Roch KG, Zhou Y, Blair PL, Grainger M, Moch JK, Haynes JD, De La Vega P, Holder AA, Batalov S, Carucci DJ, Winzeler EA, 2003. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301 : 1503–1508.
  30. Grifantini R, Bartolini E, Muzzi A, Draghi M, Frigimelica E, Berger J, Ratti G, Petracca R, Galli G, Agnusdei M, Giuliani MM, Santini L, Brunelli B, Tettelin H, Rappuoli R, Randazzo F, Grandi G, 2002. Previously unrecognized vaccine candidates against group B meningococcus identified by DNA microarrays. Nat Biotechnol 20 : 914–921.
  31. Grifantini R, Bartolini E, Muzzi A, Draghi M, Frigimelica E, Berger J, Randazzo F, Grandi G, 2002. Gene expression profile in Neisseria meningitidis and Neisseria lactamica upon host-cell contact: from basic research to vaccine development. Ann NY Acad Sci 975 : 202–216.
  32. Francis SE, Malkov VA, Oleinikor AV, Rossnagle E, Wendler JP, Mutabingwa TK, Fried M, Duffy PE, 2007. Six genes are preferentially transcribed by the circulating and sequested forms of Plasmodium falciparum parasites that infect pregnant women. Infect Immun 75 : 4838–4850.
  33. Ackerman H, Usen S, Jallow M, Sisay-Joof F, Pinder M, Kwiatkowski DP, 2005. A comparison of case-control and family-based association methods: the example of sickle-cell and malaria. Ann Hum Genet 69 : 559–565.
  34. Mackinnon MJ, Mwangi TW, Snow RW, Marsh K, Williams TN, 2005. Heritability of malaria in Africa. PLoS Med 2 : e340.
  35. Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G, Destro-Bisol G, Drousiotou A, Dangerfield B, Lefranc G, Loiselet J, Piro A, Stoneking M, Tagarelli A, Tagarelli G, Touma EH, Williams SM, Clark AG, 2001. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293 : 455–462.
  36. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES, 2002. Detecting recent positive selection in the human genome from haplotype structure. Nature 419 : 832–837.
  37. Ohashi J, Naka I, Patarapotikul J, Hananantachai H, Brittenham G, Looareesuwan S, Clark AG, Tokunaga K, 2004. Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection. Am J Hum Genet 74 : 1198–1208.
  38. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P, 2005. A haplotype map of the human genome. Nature 437 : 1299–1320.
  39. Miller LH, Mason SJ, Clyde DF, McGinniss MH, 1976. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med 295 : 302–304.
  40. Chitnis CE, Miller LH, 1994. Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J Exp Med 180 : 497–506.
  41. Yazdani SS, Shakri AR, Pattnaik P, Rizvi MM, Chitnis CE, 2006. Improvement in yield and purity of a recombinant malaria vaccine candidate based on the receptor-binding domain of Plasmodium vivax Duffy binding protein by codon optimization. Biotechnol Lett. 28 : 1109–1114.
  42. Marchini J, Cardon LR, Phillips MS, Donnelly P, 2004. The effects of human population structure on large genetic association studies. Nat Genet 36 : 512–517.
  43. Chokshi DA, Parker M, Kwiatkowski DP, 2006. Data sharing and intellectual property in a genomic epidemiology network: policies for large-scale research collaboration. Bull World Health Organ 84 : 382–387.
  • Received : 21 Aug 2006
  • Accepted : 14 Apr 2007

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