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.

The origin of malaria: mixed messages from genetic diversity

Key Points

  • The past 35 years have seen an upsurge in the prevalence of malaria, caused by a number of mutually reinforcing factors, including the spread of drug-resistant Plasmodium falciparum parasites and insecticide-resistant mosquitoes, increased population density, global warming and poverty in affected countries.

  • There is evidence to indicate that a similar rapid expansion of the P. falciparum population took place about 10,000 years ago. Understanding the population history of P. falciparum is important for determining the most effective ways to combat the present malaria epidemic, as the level of genetic diversity present in the parasite genome has important implications for the evolution of parasite resistance to drugs.

  • Studies of the levels of synonymous polymorphism in P. falciparum protein-coding sequences generally support an expansion of the parasite population 10,000 years ago. However, differences in the sets of genes analysed, and errors in some sequence database entries, have led to discrepancies in the conclusions that have been drawn from these studies.

  • Analysis of non-coding parasite sequences should provide a more accurate picture of levels of genetic variation, as they are subject to a lower levels of selective constraints than are coding sequences. However, high levels of mutation in microsatellite sequences have led to difficulties in interpreting the results of such studies, as have discrepancies in the results obtained for different genomic regions, which are likely to result from the effects of recombination.

  • Mitochondrial DNA has been used to clarify the results obtained using other methods, as it is not subject to recombination. Analysis of the P. falciparum mitochondrial genome generally supports the theory that the parasite population expanded rapidly 10,000 years ago.

  • Altogether, these studies indicate that the level of genetic variation is much lower in P. falciparum than in many other microorganisms. This has important implications for strategies to combat malaria, as it suggests that the parasite is likely to require new mutations to occur in order to develop resistance to drugs, a theory that is borne out by the fact that resistance to chloroquine has been slow to evolve.


Over the past 35 years, the incidence of malaria has increased 2–3-fold. At present, it affects 300–500 million people and causes about 1 million deaths, primarily in Africa. The continuing upsurge has come from a coincidence of drug-resistant parasites, insecticide-resistant mosquitoes, global climate change and continuing poverty and political instability. An analogous rapid increase in malaria might have taken place about 10,000 years ago. Patterns of genetic variation in mitochondrial DNA support this model, but variation in nuclear genes gives an ambiguous message. Resolving these discrepancies has implications for the evolution of drug resistance and vaccine evasion.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Distribution of malaria, and the increase in its incidence in recent years.
Figure 2: Origin and spread of chloroquine resistance.

Accession codes




  1. Breman, J. G. The ears of the hippopotamus: Manifestations, determinants, and estimates of the malaria burden. Am. J. Trop. Med. Hyg. 64, S1–S11 (2001).

    Article  Google Scholar 

  2. Sachs, J. D. A new global effort to control malaria. Science 298, 122–124 (2002).

    Article  CAS  Google Scholar 

  3. Hastings, I. M., Bray, P. G. & Ward, S. A. A requiem for chloroquine. Science 298, 74–75 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Sidhu, A. B. S., Verdier-Pinard, D. & Fidock, D. A. Chloroquire resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298, 210–213 (2002).

    Article  CAS  Google Scholar 

  6. Bradley, D. J. The particular and the general: issues of specificity and verticality in the history of malaria control. Parassitologia 40, 5–10 (1998).

    CAS  PubMed  Google Scholar 

  7. Hemingway, J. & Ranson, H. Insecticide resistance in insect vectors of human disease. Ann. Rev. Entomol. 45, 369–389 (2000).

    Article  Google Scholar 

  8. Hemingway, J., Field, L. & Vontas, J. An overview of insecticide resistance. 298, 96–97 (2002).

  9. Report of the Intergovenmental Panel on Climate Change (IPCC). Climate Change 2001: impacts, adaptation and vulnerability. Contribution of Working Group II to the Third Assessment Report of United Nations Environment Programme (IPCC, Geneva, Switzerland, 2001).

  10. World Health Organization. Press Release PR-2000-46. Third of African malaria deaths due to conflict or natural disaster. [online], (cited 11 Nov 2003), (30 June 2000).

  11. Gallup, J. L. & Sachs, J. D. The economic burden of malaria. Am. J. Trop. Med. Hyg. 64, S85–S96 (2001).

    Article  Google Scholar 

  12. Livingstone, F. B. Anthropological implications of sickle-cell gene distribution in West Africa. Am. Anthropol. 60, 533–562 (1958).

    Article  Google Scholar 

  13. Wiesenfeld, S. L. Sickle-cell trait in human biological and cultural evolution. Science 157, 1134–1140 (1967).

    Article  CAS  Google Scholar 

  14. Olago, D. O. Vegetation changes over palaeo-time scales in Africa. Climate Res. 17, 105–121 (2001).

    Article  Google Scholar 

  15. Salamini, F., Ozkan, H., Brandolini, A., Schafer-Pregl, R. & Martin, W. Genetics and geography of wild cereal domestication in the Near East. Nature Rev. Genet. 3, 429–441 (2002).

    Article  CAS  Google Scholar 

  16. Coluzzi, M., Petrarca, V. & Di Deco, M. A. Chromosomal inversion intergradation and incipient speciation in Anopheles gambiae. Boll. Zool. 52, 45–63 (1985).

    Article  Google Scholar 

  17. Coluzzi, M. The clay feet of the malaria giant and its African roots: hypotheses and inferences about origin, spread and control of Plasmodium falciparum. Parassitologia 41, 277–283 (1999).

    CAS  PubMed  Google Scholar 

  18. Boyd, M. (ed.) Malariology: A Comprehensive Survey of All Aspects of This Group of Diseases from a Global Standpoint (Saunders, Philadelphia, 1949).

    Google Scholar 

  19. Liaison Bulletin of the Malaria Programme WHO/AFRO. Severe malaria in the African region: results of a multicentre study. [online], (cited 11 Nov 2003), (April 2001).

  20. Tishkoff, S. A. et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293, 455–462 (2001).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Anderson, T. J. C., Su, X. Z., Roddam, A. & Day, K. P. Complex mutations in a high proportion of microsatellite loci from the protozoan parasite Plasmodium falciparum. Mol. Ecol. 9, 1599–1608 (2000).

    Article  CAS  Google Scholar 

  23. Rich, S. M., Licht, M. C., Hudson, R. R. & Ayala, F. J. Malaria's Eve: evidence of a recent population bottleneck throughout the world population of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 95, 4425–4430 (1998). A key paper and important stimulus to research on the population genetics of P. falciparum , which concluded from an analysis of GenBank sequences that the present parasite population derives relatively recently from a relatively small number of common ancestors.

    Article  CAS  Google Scholar 

  24. Hartl, D. L., Boyd, E. F., Bustamante, C. D. & Sawyer, S. A. in Genomics and Proteomics. (ed. Suhai, S.) 37–49 (Plenum Press, New York, 2000).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Ikemura, T. Codon usage and tRNA content in unicellular and multicellular organisms. Mol. Biol. Evol. 203, 1–13 (1985).

    Google Scholar 

  27. Volkman, S. et al. Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum. Science 298, 216–218 (2002). This paper describes the unusual distribution of single-nucleotide polymorphisms in chromosome 2 of P. falciparum , with most polymorphisms concentrated in the subtelomeric regions and with a disproportionate number present in genes encoding proteins associated with the cell membrane.

    Article  CAS  Google Scholar 

  28. Tanabe, K., Mackay, M., Goman, M. & Scaife, J. G. Allelic dimorphism in a surface antigen gene of the malaria parasite Plasmodium falciparum. J. Mol. Biol. 195, 273–287 (1987).

    Article  CAS  Google Scholar 

  29. Rich, S. M. & Ayala, F. J. Population structure and recent evolution of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 97, 6994–7001 (2000).

    Article  CAS  Google Scholar 

  30. Hughes, A. L. Adaptive Evolution of Genes and Genomes (Oxford Univ. Press, New York, 1999).

    Google Scholar 

  31. Nielsen, K. M. et al. Gene conversion as a source of nucleotide diversity in Plasmodium falciparum. Mol. Biol. Evol. 20, 726–734 (2003).

    Article  CAS  Google Scholar 

  32. Hughes, A. L. & Verra, F. Very large long–term effective population size in the virulent human malaria parasite Plasmodium falciparum. Proc. R. Soc. London B Biol. Sci. 268, 1855–1860 (2001).

    Article  CAS  Google Scholar 

  33. Barry, A. E. et al. Artefacts in sequence data from the human malaria parasite, Plasmodium falciparum. Mol. Biochem. Parasitol. 130, 143–147 (2003). A cautionary tale about the uncritical acceptance of some of the older GenBank sequences and about special problems encountered in the analysis of population genetic data from A/T-rich sequences.

    Article  CAS  Google Scholar 

  34. Gardner, M. J. et al. Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. Science 282, 1126–1132 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Volkman, S. K. et al. Recent origin of Plasmodium falciparum from a single progenitor. Science 293, 482–484 (2001).

    Article  CAS  Google Scholar 

  37. Li, W. -H. Molecular Evolution (Sinauer, Sunderland, Massachusetts, 1997).

    Google Scholar 

  38. Hartl, D. L. A Primer of Population Genetics (Sinauer, Sunderland, Massachusetts, 2000).

    Google Scholar 

  39. Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. Destabilization of tracts of simple repetitive sequences in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276 (1993).

    Article  CAS  Google Scholar 

  40. Mu, J. et al. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418, 323–326 (2002). Evidence that the average age of the most recent common ancestor for genes in chromosome 3 is substantially older than 10,000 years.

    Article  CAS  Google Scholar 

  41. Babiker, H. A. et al. Random mating in a natural population of the malaria parasite Plasmodium falciparum. Parasitol. 109, 413–421 (1994).

    Article  Google Scholar 

  42. Paul, R. E. L. et al. Mating patterns in malaria parasite populations of Papua New Guinea. Science 269, 1709–1711 (1995).

    Article  CAS  Google Scholar 

  43. Hill, W. G., Babiker, H. A., Ranfordcartwright, L. C. & Walliker, D. Estimation of inbreeding coefficients from genotypic data on multiple alleles, and application to estimation of clonality in malaria parasites. Genet. Res. 65, 53–61 (1995).

    Article  CAS  Google Scholar 

  44. Conway, D. J. et al. High recombination rate in natural populations of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 4506–4511 (1999).

    Article  CAS  Google Scholar 

  45. Anderson, T. J. C. 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 

  46. Hartl, D. L. et al. The paradoxical population genetics of Plasmodium falciparum. Trends Parasit. 18, 266–272 (2002).

    Article  Google Scholar 

  47. Conway, D. J. et al. Origin of Plasmodium falciparum malaria is traced by mitochondrial DNA. Mol. Biochem. Parasitol. 111, 163–171 (2000).

    Article  CAS  Google Scholar 

  48. Joy, D. A. et al. Early origin and recent expansion of Plasmodium falciparum. Science 300, 318–321 (2003). A study of mitochondrial DNA sequences indicating that rapid population growth of a relatively small number of lineages of P. falciparum started about 10,000 years ago.

    Article  CAS  Google Scholar 

  49. Watts, S. Epidemics and History: Disease, Power and Imperialism (Yale Univ. Press, New Haven, 1997).

    Google Scholar 

  50. Vaidya, A. B., Lashgari, M. S., Pologe, L. G. & Morrisey, J. Structural features of Plasmodium cytochrome-b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones. Mol. Biochem. Parasitol. 58, 33–42 (1993).

    Article  CAS  Google Scholar 

  51. Wellems, T. E. Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science 198, 124–126 (2002).

    Article  Google Scholar 

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

    Article  Google Scholar 

  53. Remme, J. H. F., Binka, F. & Nabarro, D. Toward a framework and indicators for monitoring Roll Back Malaria. Am. J. Trop. Med. Hyg. 64, 76–84 (2001).

    Article  CAS  Google Scholar 

  54. Anderson, R. M. & May, R. M. Infectious Diseases of Humans (Oxford Univ. Press, Oxford, UK, 1991).

    Google Scholar 

  55. Lenski, R. E. & May, R. M. The evolution of virulence in parasites and pathogens: reconciliation between two competing hypotheses. J. Theor. Biol. 169, 253–265 (1994).

    Article  CAS  Google Scholar 

  56. Day, T. On the evolution of virulence and the relationship between various measures of mortality. Proc. R. Soc. Lond. B Biol. Sci. 269, 1317–1323 (2002).

    Article  Google Scholar 

  57. Day, T. & Burns, J. G. A consideration of patterns of virulence arising from host–parasite coevolution. Evolution 57, 671–676 (2003).

    Article  Google Scholar 

  58. Ewald, P. W. Evolution of Infectious Diseases (Oxford Univ. Press, Oxford, UK, 1994).

    Google Scholar 

  59. Day, T. Parasite transmission modes and the evolution of virulence. Evolution 55, 2389–2400 (2001).

    Article  CAS  Google Scholar 

  60. Ganusov, V. V. & Antia, R. Trade-offs and the evolution of virulence of microparasites: do details matter? Theor. Popul. Biol. 64, 211–220 (2003).

    Article  Google Scholar 

  61. Rogers, A. R. & Harpending, H. Population growth makes waves in the distribution of pairwise genetic differences. Mol. Biol. Evol. 9, 552–569 (1992).

    CAS  PubMed  Google Scholar 

  62. Harpending, H. C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).

    Article  CAS  Google Scholar 

  63. Harpending, H. C. Signature of ancient population growth in a low–resolution mitochondrial DNA mismatch distribution. Human Biol. 66, 591–600 (1994).

    CAS  PubMed  Google Scholar 

  64. Ramos–Onsins, S. E. & Rozas, J. Statistical properties of new neutrality tests against population growth. Mol. Biol. Evol. 19, 2092–2100 (2002).

    Article  Google Scholar 

  65. Ray, N., Currat, M. & Excoffier, L. Intra-deme molecular diversity in spatially expanding populations. Mol. Biol. Evol. 20, 76–86 (2003).

    Article  CAS  Google Scholar 

Download references


By rights this piece should have many coauthors — the collaborators whose continuing support and advice have made it possible. I am very grateful to these many colleagues and collaborators, chiefly among them D. Wirth, K. Day, E. Lozovsky and S. Volkman. I am also grateful for the contributions of K. M. Nielsen, S. A. Sawyer, E. Winzeler, A. Barry, K. Amodu, T. Bedford, E. Lyons, M. Zilversmit, M. Choi and M. White, and for the support of the National Institutes of Health, the Ellison Medical Foundation and the Burroughs-Wellcome Fund.

Author information

Authors and Affiliations


Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links




Plasmodium falciparum


Daniel L. Hartl's laboratory

Malaria Foundation International

Roll Back Malaria

The Plasmodium genome resource

What is malaria?

WHO/TDR malaria database



A measure of the harm that an infectious disease inflicts on infected individuals, estimated variously as the case-fatality rate, the reduction in expected lifespan or the lethal dose of the infectious agent.


The number of deaths due to a disease expressed as a percentage of total cases.


Cases of malaria that are marked by one or more of the following symptoms: coma, convulsions, a severe drop in blood pressure, difficulty in breathing, jaundice, blood in the urine, extreme weakness or prostration, kidney impairment, severe anaemia or hypoglycaemia.


A polymorphism in a population that results in a difference in the number of tandem repeats of a short (1–8 bp) DNA sequence.


Aberrant replication across regions of DNA that contain short, tandemly repeated sequences that results in an increase or decrease in the number of repeats present in the daughter molecules.


A single-nucleotide polymorphism in a coding region that results in an amino-acid replacement.


A single-nucleotide polymorphism in a coding region that does not result in an amino-acid replacement.


Nonrandom usage of synonymous codons, which specify the same amino acid in a polypeptide chain.


Products of one or more alleles that result in inherited variants of a particular molecule, usually a protein.


A process in which the sequence of nucleotides in a gene or allele is changed by DNA-repair mechanisms, using the nucleotide sequence of a related gene or allele as the template for repair.


The convergence, going backwards in time, of two or more gene lineages onto a single common ancestor.


A method of statistical estimation that stipulates an underlying model of a process and that estimates any parameter as the value that maximizes the probability of the observed data given the correctness of the model.


A restriction on the level or type of polymorphism that is likely to be found in a population owing to deleterious effects of the polymorphism on the ability of their carriers to survive and reproduce.


(SNP). A position in a genomic DNA sequence in which the particular nucleotide pair that is present can differ from one individual (or chromosome) to the next; it normally refers to genetic variation that is common in the population, and excludes rare mutational variants.


A process of DNA repair in which a mispaired region of a DNA duplex is excised and replaced by resynthesis using the remaining strand as a template.


The rapid increase in the frequency of a new favourable mutation to displace, or nearly displace, other alleles of the gene.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hartl, D. The origin of malaria: mixed messages from genetic diversity. Nat Rev Microbiol 2, 15–22 (2004).

Download citation

  • 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