Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome variation and evolution of the malaria parasite Plasmodium falciparum

A Corrigendum to this article was published on 01 April 2007

A Corrigendum to this article was published on 01 March 2007

This article has been updated


Infections with the malaria parasite Plasmodium falciparum result in more than 1 million deaths each year worldwide1. Deciphering the evolutionary history and genetic variation of P. falciparum is critical for understanding the evolution of drug resistance, identifying potential vaccine candidates and appreciating the effect of parasite variation on prevalence and severity of malaria in humans. Most studies of natural variation in P. falciparum have been either in depth over small genomic regions (up to the size of a small chromosome2) or genome wide but only at low resolution3. In an effort to complement these studies with genome-wide data, we undertook shotgun sequencing of a Ghanaian clinical isolate (with fivefold coverage), the IT laboratory isolate (with onefold coverage) and the chimpanzee parasite P. reichenowi (with twofold coverage). We compared these sequences with the fully sequenced P. falciparum 3D7 isolate genome4. We describe the most salient features of P. falciparum polymorphism and adaptive evolution with relation to gene function, transcript and protein expression and cellular localization. This analysis uncovers the primary evolutionary changes that have occurred since the P. falciparum–P. reichenowi speciation and changes that are occurring within P. falciparum.

NOTE: In the original version of this paper, the authors failed to acknowledge that sequencing of the P. falciparum IT laboratory isolate was funded by a European Union 6th Framework Program grant to the BioMalPar Consortium (contract number LSHP-LT-2004-503578). This error has been corrected in the PDF version of the article.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Evolutionary rates correlate with total gene expression levels.
Figure 2: Evolutionary rates in the context of gene expression during development.
Figure 3: Evolutionary rate in the context of gene function.

Similar content being viewed by others

Accession codes



Change history

  • 08 February 2007

    In the original version of this paper, the authors failed to acknowledge that sequencing of the P. falciparum IT laboratory isolate was funded by a European Union 6th Framework Program grant to the BioMalPar Consortium (contract number LSHP-LT-2004-503578). This error has been corrected in the PDF version of the article.


  1. Korenromp, E., Miller, J., Nahlen, B., Wardlaw, T. & Young, M. World Malaria Report 2005 (Roll Back Malaria Partnership, Geneva, 2005).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Anderson, T.J. Mapping drug resistance genes in Plasmodium falciparum by genome-wide association. Curr. Drug Targets Infect. Disord. 4, 65–78 (2004).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Ning, Z., Cox, A.J. & Mullikin, J.C. SSAHA: a fast search method for large DNA databases. Genome Res. 11, 1725–1729 (2001).

    Article  CAS  Google Scholar 

  6. Anderson, T.J. et al. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol. Biol. Evol. 17, 1467–1482 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Carret, C.K. et al. Microarray-based comparative genomic analyses of the human malaria parasite Plasmodium falciparum using Affymetrix arrays. Mol. Biochem. Parasitol. 144, 177–186 (2005).

    Article  CAS  Google Scholar 

  9. Yang, Z. & Bielawski, J.P. Statistical methods for detecting molecular adaptation. Trends Ecol. Evol. 15, 496–503 (2000).

    Article  CAS  Google Scholar 

  10. McDonald, J.H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654 (1991).

    Article  CAS  Google Scholar 

  11. Rocha, E.P. The quest for the universals of protein evolution. Trends Genet. 22, 412–416 (2006).

    Article  CAS  Google Scholar 

  12. Florens, L. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520–526 (2002).

    Article  CAS  Google Scholar 

  13. Le Roch, K.G. et al. Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. Genome Res. 14, 2308–2318 (2004).

    Article  CAS  Google Scholar 

  14. Bozdech, Z. et al. The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum. PLoS Biol. 1, E5 (2003).

    Article  Google Scholar 

  15. Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).

    Article  CAS  Google Scholar 

  16. Marti, M., Good, R.T., Rug, M., Knuepfer, E. & Cowman, A.F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004).

    Article  CAS  Google Scholar 

  17. Hall, N. et al. A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses. Science 307, 82–86 (2005).

    Article  CAS  Google Scholar 

  18. Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005).

    Article  Google Scholar 

  19. Garnham, P.C.C. & Duggan, A.J. Malaria Parasites and Other Haemosporidia (Blackwell Scientific, Oxford, 1996).

    Google Scholar 

  20. Martin, M.J., Rayner, J.C., Gagneux, P., Barnwell, J.W. & Varki, A. Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc. Natl. Acad. Sci. USA 102, 12819–12824 (2005).

    Article  CAS  Google Scholar 

  21. Winter, G. et al. SURFIN is a polymorphic antigen expressed on Plasmodium falciparum merozoites and infected erythrocytes. J. Exp. Med. 201, 1853–1863 (2005).

    Article  CAS  Google Scholar 

  22. Li, F. et al. Plasmodium ookinete-secreted proteins secreted through a common micronemal pathway are targets of blocking malaria transmission. J. Biol. Chem. 279, 26635–26644 (2004).

    Article  CAS  Google Scholar 

  23. Mu, J. et al. Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome. Nat. Genet. advance online publication 10 December 2006 (doi:10.1038/ng1924).

  24. Volkman, S.K. et al. A genome-wide map of diversity in Plasmodium falciparum. Nat. Genet. advance online publication 10 December 2006 (doi:10.1038/ng1930).

  25. Horrocks, P., Kyes, S., Pinches, R., Christodoulou, Z. & Newbold, C. Transcription of subtelomerically located var gene variant in Plasmodium falciparum appears to require the truncation of an adjacent var gene. Mol. Biochem. Parasitol. 134, 193–199 (2004).

    Article  CAS  Google Scholar 

  26. Bowman, S. et al. The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum. Nature 400, 532–538 (1999).

    Article  CAS  Google Scholar 

  27. Altshuler, D. et al. An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516 (2000).

    Article  CAS  Google Scholar 

  28. Yang, Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl. Biosci. 13, 555–556 (1997).

    CAS  Google Scholar 

  29. Rand, D.M. & Kann, L.M. Excess amino acid polymorphism in mitochondrial DNA: contrasts among genes from Drosophila, mice, and humans. Mol. Biol. Evol. 13, 735–748 (1996).

    Article  CAS  Google Scholar 

  30. Young, J.A. et al. The Plasmodium falciparum sexual development transcriptome: a microarray analysis using ontology-based pattern identification. Mol. Biochem. Parasitol. 143, 67–79 (2005).

    Article  CAS  Google Scholar 

Download references


We thank the Pathogen Sequencing teams for producing the sequence data used in this study, P. Horrocks and B. Pinches for the supply of DNA from the IT isolate and M. Marti for the list of PEXEL motif–containing genes. This study was funded by the Wellcome Trust through its support of the Pathogen Sequencing Unit and E.T.D.'s group at the Wellcome Trust Sanger Institute.

Author information

Authors and Affiliations



D.J. processed SSAHA data, produced diversity and evolutionary measures, analyzed the data and wrote the manuscript. E.T.D. and M.B. directed the project and assisted with analysis of the data and writing of the manuscript. A.P. and A.B. assisted with analysis and processing of the data and biological interpretation of the data. A.T. collected the P. reichenowi sample and extracted DNA. K.S. assisted with data processing and analysis. A.C. provided SSAHA mapping. J.S. assisted with data processing. C.I. resequenced genes and manually verified SNPs. A.-C.U. assisted with parasite DNA extraction. S. Krishna assisted in biological interpretation of the data and parasitology. C.N. shaped some of the initial ideas for the project, assisted in biological interpretation of the data and assisted with parasite DNA extraction. S. Kyes grew the IT parasite and purified and extracted DNA from parasites.

Corresponding authors

Correspondence to Emmanouil T Dermitzakis or Matthew Berriman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The distributions of dN/dS estimates are negatively skewed. (PDF 138 kb)

Supplementary Fig. 2

Correlations of dN/dS and expression level are robust to the use of different expression data and to subsets of variation data called using SSAHA. (PDF 415 kb)

Supplementary Fig. 3

Consistent relative differences in evolutionary rates between stage-specific genes were observed with protein and microarray data. (PDF 161 kb)

Supplementary Table 1 (XLS 2027 kb)

Supplementary Methods (PDF 114 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeffares, D., Pain, A., Berry, A. et al. Genome variation and evolution of the malaria parasite Plasmodium falciparum. Nat Genet 39, 120–125 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing