Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
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.
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References
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).
Sachs, J. D. A new global effort to control malaria. Science 298, 122–124 (2002).
Hastings, I. M., Bray, P. G. & Ward, S. A. A requiem for chloroquine. Science 298, 74–75 (2002).
Wootton, J. C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323 (2002).
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).
Bradley, D. J. The particular and the general: issues of specificity and verticality in the history of malaria control. Parassitologia 40, 5–10 (1998).
Hemingway, J. & Ranson, H. Insecticide resistance in insect vectors of human disease. Ann. Rev. Entomol. 45, 369–389 (2000).
Hemingway, J., Field, L. & Vontas, J. An overview of insecticide resistance. 298, 96–97 (2002).
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).
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).
Gallup, J. L. & Sachs, J. D. The economic burden of malaria. Am. J. Trop. Med. Hyg. 64, S85–S96 (2001).
Livingstone, F. B. Anthropological implications of sickle-cell gene distribution in West Africa. Am. Anthropol. 60, 533–562 (1958).
Wiesenfeld, S. L. Sickle-cell trait in human biological and cultural evolution. Science 157, 1134–1140 (1967).
Olago, D. O. Vegetation changes over palaeo-time scales in Africa. Climate Res. 17, 105–121 (2001).
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).
Coluzzi, M., Petrarca, V. & Di Deco, M. A. Chromosomal inversion intergradation and incipient speciation in Anopheles gambiae. Boll. Zool. 52, 45–63 (1985).
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).
Boyd, M. (ed.) Malariology: A Comprehensive Survey of All Aspects of This Group of Diseases from a Global Standpoint (Saunders, Philadelphia, 1949).
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).
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).
Su, X. -Z. et al. A genetic map and recombination parameters of the human malaria parasite Plasmodium falcipirum. Science 286, 1351–1353 (1999).
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).
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.
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).
Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002).
Ikemura, T. Codon usage and tRNA content in unicellular and multicellular organisms. Mol. Biol. Evol. 203, 1–13 (1985).
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.
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).
Rich, S. M. & Ayala, F. J. Population structure and recent evolution of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 97, 6994–7001 (2000).
Hughes, A. L. Adaptive Evolution of Genes and Genomes (Oxford Univ. Press, New York, 1999).
Nielsen, K. M. et al. Gene conversion as a source of nucleotide diversity in Plasmodium falciparum. Mol. Biol. Evol. 20, 726–734 (2003).
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).
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.
Gardner, M. J. et al. Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. Science 282, 1126–1132 (1998).
Bowman, S. et al. The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum. Nature 400, 532–538 (1999).
Volkman, S. K. et al. Recent origin of Plasmodium falciparum from a single progenitor. Science 293, 482–484 (2001).
Li, W. -H. Molecular Evolution (Sinauer, Sunderland, Massachusetts, 1997).
Hartl, D. L. A Primer of Population Genetics (Sinauer, Sunderland, Massachusetts, 2000).
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).
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.
Babiker, H. A. et al. Random mating in a natural population of the malaria parasite Plasmodium falciparum. Parasitol. 109, 413–421 (1994).
Paul, R. E. L. et al. Mating patterns in malaria parasite populations of Papua New Guinea. Science 269, 1709–1711 (1995).
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).
Conway, D. J. et al. High recombination rate in natural populations of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 4506–4511 (1999).
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).
Hartl, D. L. et al. The paradoxical population genetics of Plasmodium falciparum. Trends Parasit. 18, 266–272 (2002).
Conway, D. J. et al. Origin of Plasmodium falciparum malaria is traced by mitochondrial DNA. Mol. Biochem. Parasitol. 111, 163–171 (2000).
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.
Watts, S. Epidemics and History: Disease, Power and Imperialism (Yale Univ. Press, New Haven, 1997).
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).
Wellems, T. E. Plasmodium chloroquine resistance and the search for a replacement antimalarial drug. Science 198, 124–126 (2002).
Wootten, J. C. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 418, 320–323 (2002).
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).
Anderson, R. M. & May, R. M. Infectious Diseases of Humans (Oxford Univ. Press, Oxford, UK, 1991).
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).
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).
Day, T. & Burns, J. G. A consideration of patterns of virulence arising from host–parasite coevolution. Evolution 57, 671–676 (2003).
Ewald, P. W. Evolution of Infectious Diseases (Oxford Univ. Press, Oxford, UK, 1994).
Day, T. Parasite transmission modes and the evolution of virulence. Evolution 55, 2389–2400 (2001).
Ganusov, V. V. & Antia, R. Trade-offs and the evolution of virulence of microparasites: do details matter? Theor. Popul. Biol. 64, 211–220 (2003).
Rogers, A. R. & Harpending, H. Population growth makes waves in the distribution of pairwise genetic differences. Mol. Biol. Evol. 9, 552–569 (1992).
Harpending, H. C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).
Harpending, H. C. Signature of ancient population growth in a low–resolution mitochondrial DNA mismatch distribution. Human Biol. 66, 591–600 (1994).
Ramos–Onsins, S. E. & Rozas, J. Statistical properties of new neutrality tests against population growth. Mol. Biol. Evol. 19, 2092–2100 (2002).
Ray, N., Currat, M. & Excoffier, L. Intra-deme molecular diversity in spatially expanding populations. Mol. Biol. Evol. 20, 76–86 (2003).
Acknowledgements
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.
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Glossary
- VIRULENCE
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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.
- CASE-FATALITY RATE
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The number of deaths due to a disease expressed as a percentage of total cases.
- SEVERE MALARIA
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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.
- MICROSATELLITE POLYMORPHISM
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A polymorphism in a population that results in a difference in the number of tandem repeats of a short (1–8 bp) DNA sequence.
- REPLICATION SLIPPAGE
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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.
- NONSYNONYMOUS POLYMORPHISM
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A single-nucleotide polymorphism in a coding region that results in an amino-acid replacement.
- SYNONYMOUS POLYMORPHISM
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A single-nucleotide polymorphism in a coding region that does not result in an amino-acid replacement.
- CODON-USAGE BIAS
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Nonrandom usage of synonymous codons, which specify the same amino acid in a polypeptide chain.
- ALLOTYPES
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Products of one or more alleles that result in inherited variants of a particular molecule, usually a protein.
- GENE CONVERSION
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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.
- COALESCENT
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The convergence, going backwards in time, of two or more gene lineages onto a single common ancestor.
- MAXIMUM LIKELIHOOD
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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.
- SELECTIVE CONSTRAINT
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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.
- SINGLE-NUCLEOTIDE POLYMORPHISM
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(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.
- MISMATCH REPAIR
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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.
- SELECTIVE SWEEP
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The rapid increase in the frequency of a new favourable mutation to displace, or nearly displace, other alleles of the gene.
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Hartl, D. The origin of malaria: mixed messages from genetic diversity. Nat Rev Microbiol 2, 15–22 (2004). https://doi.org/10.1038/nrmicro795
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DOI: https://doi.org/10.1038/nrmicro795
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