Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum (original) (raw)

Nature volume 418, pages 320–323 (2002)Cite this article

Abstract

Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates1,2,3,4 to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America5, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map6, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt7 and at least four CQR founder events. This disequilibrium and its decay rate in the _pfcrt_-flanking region are consistent with strong directional selective sweeps occurring over only ∼20–80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.

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

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Rich, S. M. & Ayala, F. J. The recent origin of allelic variation in antigenic determinants of Plasmodium falciparum. Genetics 150, 515–517 (1998)
    CAS PubMed PubMed Central Google Scholar
  2. Volkman, S. K. et al. Recent origin of Plasmodium falciparum from a single progenitor. Science 293, 482–484 (2001)
    Article CAS Google Scholar
  3. Hughes, A. L. & Verra, F. Very large long-term effective population size in the virulent human malaria parasite Plasmodium falciparum. Proc. R. Soc. Lond. B 268, 1855–1860 (2001)
    Article CAS Google Scholar
  4. Hey, J. Parasite populations: the puzzle of Plasmodium. Curr. Biol. 9, R565–R567 (1999)
    Article CAS Google Scholar
  5. Payne, D. Spread of chloroquine resistance in Plasmodium falciparum. Parasitol. Today 3, 241–246 (1987)
    Article CAS Google Scholar
  6. Su, X. et al. A genetic map and recombination parameters of the human malaria parasite Plasmodium falciparum. Science 286, 1351–1353 (1999)
    Article CAS Google Scholar
  7. Fidock, D. A. et al. Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6, 861–871 (2000)
    Article CAS Google Scholar
  8. 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
  9. Escalante, A. A., Barrio, E. & Ayala, F. J. Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene. Mol. Biol. Evol. 12, 616–626 (1995)
    CAS PubMed Google Scholar
  10. 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
  11. Djimde, A. et al. A molecular marker for chloroquine-resistant falciparum malaria. N. Engl. J. Med. 344, 257–263 (2001)
    Article CAS Google Scholar
  12. Dorsey, G., Kamya, M. R., Singh, A. & Rosenthal, P. J. Polymorphisms in the Plasmodium falciparum pfcrt and pfmdr-1 genes and clinical response to chloroquine in Kampala, Uganda. J. Infect. Dis. 183, 1417–1420 (2001)
    Article CAS Google Scholar
  13. Conway, D. J. et al. High recombination rate in natural populations of Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 4506–4511 (1999)
    Article ADS CAS Google Scholar
  14. Hill, W. G., Babiker, H. A., Ranford-Cartwright, 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
  15. Walliker, D., Babiker, H. & Ranford Cartwright, L. in Malaria: Parasite Biology, Pathogenesis, and Protection (ed. Sherman, I. W.) 235–252 (American Society for Microbiology, Washington DC, 1998)
    Google Scholar
  16. Paul, R. E. et al. Mating patterns in malaria parasite populations of Papua New Guinea. Science 269, 1709–1711 (1995)
    Article ADS CAS Google Scholar
  17. Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673–675 (1976)
    Article ADS CAS Google Scholar
  18. Su, X., 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 Google Scholar
  19. Dye, C. & Williams, B. G. Multigenic drug resistance among inbred malaria parasites. Proc. R. Soc. Lond. B 264, 61–67 (1997)
    Article ADS CAS Google Scholar
  20. Nomura, T. et al. Evidence for different mechanisms of chloroquine resistance in 2 Plasmodium species that cause human malaria. J. Infect. Dis. 183, 1653–1561 (2001)
    Article CAS Google Scholar

Download references

Acknowledgements

We thank various investigators who provided the isolates over the years, S. Davis-Hayman, D. Joy, K. Hayton and B. Marshall for critical reading of the manuscript and editorial assistance, and T. Wellems, L. Miller and D. Lipman for support and encouragement. The opinions of the authors do not necessarily reflect those of the US army or the Department of Defense.

Author information

Authors and Affiliations

  1. Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, 20894-6075, USA
    John C. Wootton
  2. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892-0425, USA
    Xiaorong Feng, Roland A. Cooper, Jianbing Mu, Dror I. Baruch, Alan J. Magill & Xin-zhuan Su
  3. Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, 46556-016, USA
    Michael T. Ferdig
  4. Division of Communicable Disease and Immunology, Walter Reed Army Institute of Research, 20307-5100, Washington DC, USA
    Alan J. Magill

Authors

  1. John C. Wootton
    You can also search for this author inPubMed Google Scholar
  2. Xiaorong Feng
    You can also search for this author inPubMed Google Scholar
  3. Michael T. Ferdig
    You can also search for this author inPubMed Google Scholar
  4. Roland A. Cooper
    You can also search for this author inPubMed Google Scholar
  5. Jianbing Mu
    You can also search for this author inPubMed Google Scholar
  6. Dror I. Baruch
    You can also search for this author inPubMed Google Scholar
  7. Alan J. Magill
    You can also search for this author inPubMed Google Scholar
  8. Xin-zhuan Su
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toXin-zhuan Su.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Wootton, J., Feng, X., Ferdig, M. et al. Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.Nature 418, 320–323 (2002). https://doi.org/10.1038/nature00813

Download citation

Associated content