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Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome

Nature Genetics volume 39, pages 126–130 (2007)Cite this article

Abstract

One goal in sequencing the Plasmodium falciparum genome, the agent of the most lethal form of malaria, is to discover vaccine and drug targets1. However, identifying those targets in a genome in which ∼60% of genes have unknown functions is an enormous challenge. Because the majority of known malaria antigens and drug-resistant genes are highly polymorphic and under various selective pressures2,3,4,5,6, genome-wide analysis for signatures of selection may lead to discovery of new vaccine and drug candidates. Here we surveyed 3,539 P. falciparum genes (∼65% of the predicted genes) for polymorphisms and identified various highly polymorphic loci and genes, some of which encode new antigens that we confirmed using human immune sera. Our collections of genome-wide SNPs (∼65% nonsynonymous) and polymorphic microsatellites and indels provide a high-resolution map (one marker per ∼4 kb) for mapping parasite traits and studying parasite populations. In addition, we report new antigens, providing urgently needed vaccine candidates for disease control.

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Figure 1: Physical maps showing distribution of polymorphic sites across 14 P. falciparum chromosomes.
Figure 2: Immunoblots of candidate antigens expressed in vitro.

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References

  1. Gardner, M.J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Polley, S.D. & Conway, D.J. Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene. Genetics 158, 1505–1512 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Conway, D.J. et al. A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat. Med. 6, 689–692 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Volkman, S.K. et al. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science 298, 216–218 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Wootton, J.C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Roper, C. et al. Intercontinental spread of pyrimethamine–resistant malaria. Science 305, 1124 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Wellems, T.E., Walker–Jonah, A. & Panton, L.J. Genetic mapping of the chloroquine–resistance locus on Plasmodium falciparum chromosome 7. Proc. Natl. Acad. Sci. USA 88, 3382–3386 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Su, X.-z., Kirkman, L.A., Fujioka, H. & Wellems, T.E. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine–resistant P. falciparum in Southeast Asia and Africa. Cell 91, 593–603 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Vaidya, A.B. et al. A genetic locus on Plasmodium falciparum chromosome 12 linked to a defect in mosquito–infectivity and male gametogenesis. Mol. Biochem. Parasitol. 69, 65–71 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, P., Read, M., Sims, P.F. & Hyde, J.E. Sulfadoxine resistance in the human malaria parasite Plasmodium falciparum is determined by mutations in dihydropteroate synthetase and an additional factor associated with folate utilization. Mol. Microbiol. 23, 979–986 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Mu, J. et al. Recombination hotspots and population structure in Plasmodium falciparum. PLoS Biol. 3, e335 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Su, X.-z. et al. A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286, 1351–1353 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Lindblad–Toh, K. et al. Large–scale discovery and genotyping of single–nucleotide polymorphisms in the mouse. Nat. Genet. 24, 381–386 (2000).

    Article  PubMed  Google Scholar 

  14. Kennedy, G.C. et al. Large–scale genotyping of complex DNA. Nat. Biotechnol. 21, 1233–1237 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Hardenbol, P. et al. Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay. Genome Res. 15, 269–275 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gunderson, K.L., Steemers, F.J., Lee, G., Mendoza, L.G. & Chee, M.S. A genome–wide scalable SNP genotyping assay using microarray technology. Nat. Genet. 37, 549–554 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Hey, J. Parasite populations: the puzzle of Plasmodium. Curr. Biol. 9, R565–R567 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Mu, J. et al. Chromosome–wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418, 323–326 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Baum, J., Thomas, A.W. & Conway, D.J. Evidence for diversifying selection on erythrocyte–binding antigens of Plasmodium falciparum and P. vivax. Genetics 163, 1327–1336 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baruch, D.I. et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Su, X.-z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum–infected erythrocytes. Cell 82, 89–100 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Smith, J.D. et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Trimnell, A. et al. Global genetic diversity and evolution of var genes associated with placental and severe childhood malaria. Mol. Biochem. Parasitol. 148, 169–180 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Hudson, R.R. & Kaplan, N.L. The coalescent process in models with selection and recombination. Genetics 120, 831–840 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nordborg, M., Charlesworth, B. & Charlesworth, D. Increased levels of polymorphism surrounding selectively maintained sites in highly selfing species. Proc. R. Soc. Lond. B 263, 1033–1039 (1996).

    Article  Google Scholar 

  26. Charlesworth, D. Balancing selection and its effects on sequences in nearby genome regions. PLoS Genet. 2, e64 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sato, S. & Wilson, R.J. The plastid of Plasmodium spp.: a target for inhibitors. Curr. Top. Microbiol. Immunol. 295, 251–273 (2005).

    CAS  PubMed  Google Scholar 

  28. Kissinger, J.C. et al. The Plasmodium genome database. Nature 419, 490–492 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Myers, S.R. & Griffiths, R.C. Bounds on the minimum number of recombination events in a sample history. Genetics 163, 375–394 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank C. Long and R. Fairhurst for pooled immune human sera and National Institute of Allergy and Infectious Disease (NIAID) intramural editor B.R. Marshall for assistance. This work was supported by the Division of Intramural Research of the NIAID as well as by the US National Institutes of Health, the National Academies Keck Genome Initiative and the Human Frontiers in Science Program (P.A.).

Author information

Authors and Affiliations

  1. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jianbing Mu, Junhui Duan, Karl Seydel & Xin-zhuan Su

  2. Department of Genetics, North Carolina State University, Raleigh, 27695-7614, North Carolina, USA

    Philip Awadalla, Kate M McGee & Jon Keebler

  3. Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK

    Gilean A T McVean

Authors
  1. Jianbing Mu
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  2. Philip Awadalla
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  3. Junhui Duan
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  4. Kate M McGee
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  5. Jon Keebler
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  6. Karl Seydel
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  7. Gilean A T McVean
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  8. Xin-zhuan Su
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Contributions

J.M.: DNA amplification, sequencing and data analysis; J.D.: DNA amplification and sequencing; K.S.: primer design; K.M.M. and J.K.: software and database development and data analysis; G.A.T.M.: manuscript preparation; P.A.: software and database development, data analysis and manuscript preparation; X-z.S.: project design, data analysis and manuscript preparation.

Corresponding authors

Correspondence to Philip Awadalla or Xin-zhuan Su.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Distribution of SNPs among 3,539 genes or gene fragments from five P. falciparum isolates. (PDF 3 kb)

Supplementary Fig. 2

Relationship of SNP density and chromosome size. (PDF 4 kb)

Supplementary Fig. 3

Highly polymorphic genes grouped according to GO functional terms. (PDF 68 kb)

Supplementary Fig. 4

Plots of nucleotide polymorphism (Watterson's theta) per gene on the 14 chromosome of Plasmodium falciparum. (PDF 426 kb)

Supplementary Table 1

Genes and sequences surveyed, SNP alleles, and diversity statistics. (XLS 1797 kb)

Supplementary Table 2

DNA sequences and SNPs obtained from 99 worldwide isolates. (PDF 90 kb)

Supplementary Table 3

Chromosomal loci with five or more consecutive polymorphic genes. (PDF 44 kb)

Supplementary Table 4

Polymorphic genes expressed in cell free E. coli rapid translation system. (PDF 137 kb)

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Mu, J., Awadalla, P., Duan, J. et al. Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nat Genet 39, 126–130 (2007). https://doi.org/10.1038/ng1924

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