Skip to main content
    • Aa
    • Aa

Genome sequences reveal divergence times of malaria parasite lineages

  • JOANA C. SILVA (a1) (a2), AMY EGAN (a2), ROBERT FRIEDMAN (a3), JAMES B. MUNRO (a1) (a2), JANE M. CARLTON (a4) and AUSTIN L. HUGHES (a3)...

The evolutionary history of human malaria parasites (genus Plasmodium) has long been a subject of speculation and controversy. The complete genome sequences of the two most widespread human malaria parasites, P. falciparum and P. vivax, and of the monkey parasite P. knowlesi are now available, together with the draft genomes of the chimpanzee parasite P. reichenowi, three rodent parasites, P. yoelii yoelli, P. berghei and P. chabaudi chabaudi, and one avian parasite, P. gallinaceum.


We present here an analysis of 45 orthologous gene sequences across the eight species that resolves the relationships of major Plasmodium lineages, and provides the first comprehensive dating of the age of those groups.


Our analyses support the hypothesis that the last common ancestor of P. falciparum and the chimpanzee parasite P. reichenowi occurred around the time of the human-chimpanzee divergence. P. falciparum infections of African apes are most likely derived from humans and not the other way around. On the other hand, P. vivax, split from the monkey parasite P. knowlesi in the much more distant past, during the time that encompasses the separation of the Great Apes and Old World Monkeys.


The results support an ancient association between malaria parasites and their primate hosts, including humans.

Corresponding author
*Corresponding author: Tel: +1-803-777-9186. E-mail:
Hide All
Abascal F., Zardoya R. and Posada D. (2005). ProtTest: Selection of best-fit models of protein evolution. Bioinformatics 21, 21042105.
Anderson T. J., Haubold B., Williams J. T., Estrada-Franco J. G., Richardson L., Mollinedo R., Bockarie M., Mokili J., Mharakurwa S., French N., Whitworth J., Velez I. D., Brockman A. H., Nosten F., Ferreira M. U. and Day K. P. (2000). Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Molecular Biology and Evolution 17, 14671482.
Aquadro C. F., Dumont V. B. and Reed F. A. (2001). Genome-wide variation in the human and fruitfly: a comparison. Current Opinion in Genetics and Development 11, 627634.
Caldecott J. and Miles L. (2005). World Atlas of Great Apes and their Conservation. University of California Press, Berkeley.
Caswell J., Mallick S., Richter D. J., Neubauer J., Schirmer C., Gnerre S. and Reich D. (2008). Analysis of chimpanzee history based on genome sequence alignments. PLoS Genetics 4, e1000057.
Cox-Singh J., Davis T. M., Lee K. S., Shamsul S. S., Matusop A., Ratnam S., Rahman H. A., Conway D. J. and Singh B. (2008). Plasmodium knowlesi malaria in humans is widely distributed and potentially life threatening. Clinical Infectious Diseases 46, 165171.
Dávalos L. M. and Perkins S. L. (2008). Saturation and base composition bias explain phylogenomic conflict in Plasmodium. Genomics 91, 433442.
Drummond A. J. and Rambaut A. (2007). BEAST: Bayesian evolutionary analysis by sampling trees. BMC Evolutionary Biology 7, 214.
Duval L., Fourment M., Nerrienet E., Rousset D., Sadeuh S. A., Goodman S. M., Andriaholinirina N. V., Randrianarivelojosia M., Paul R. E., Robert V., Ayala F. J. and Ariey F. (2010). African apes as reservoirs of Plasmodium falciparum and the origin and diversification of the Laverania subgenus. Proceedings of the National Academy of Sciences, USA 107, 1056110566.
Egan A., Mahurkar A., Crabtree J., Badger J. H., Carlton J. M. and Silva J. C. (2008). IDEA: Interactive Display for Evolutionary Analyses. BMC Bioinformatics 9, 524.
Escalante A. A. and Ayala F. J. (1994). Phylogeny of the malarial genus Plasmodium, derived from rRNA gene sequences. Proceedings of the National Academy of Sciences, USA 91, 1137311377.
Escalante A. A., Cornejo O. E., Freeland D. E., Poe A. C., Durrego E., Collins W. E. and Lal A. A. (2005). A monkey's tale: the origin of Plasmodium vivax as a human malaria parasite. Proceedings of the National Academy of Sciences, USA 102, 19801985.
Escalante A. A., Freeland D. E., Collins W. E. and Lal A. A. (1998). The evolution of primate malaria parasites based on the gene encoding cytochrome b from the linear mitochondrial genome. Proceedings of the National Academy of Sciences, USA 95, 81248129.
Felsenstein J. (1985). Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39, 783791.
Garamszegi L. Z. (2009). Patterns of co-speciation and host switching in primate malaria parasites. Malaria Journal 8, 110.
Glazko G. V. and Nei M. (2003). Estimation of divergence times for major lineages of primate species. Molecular Biology and Evolution 20, 424434.
Harcourt A. H. (1981). Can Uganda's gorillas survive? – A survey of the Bwindi Forest Reserve. Biological Conservation 19, 269282.
Hayakawa T., Culleton R., Otani H., Horii T. and Tanabe K. (2008). Big bang in the evolution of extant malaria parasites. Molecular Biology and Evolution 25, 22332239.
Honeycutt R. L. (2009). Rodents (Rodentia). In The Timetree of Life (ed. Hedges S. B. and Kumar S.), pp. 490494. Oxford University Press, New York.
Hopkin M. (2007). Gorillas on the list. Nature 449, 127.
Hotez P. J., Molyneux D. H., Fenwick A., Ottesen E., Ehrlich Sachs S. and Sachs J. D. (2006). Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Medicine 3, e102.
Hughes A. L., and French J. O. (2007). Homologous recombination and the pattern of nucleotide substitution in Ehrlichia ruminantium. Gene 387, 3137.
Hughes A. L. and Nei M. (1990). Evolutionary relationships of class II major-histocompatibility-complex genes in mammals. Molecular Biology and Evolution 7, 491514.
Hughes A. L. and Verra F. (2001). Very large long-term effective population size in the virulent human malaria parasite Plasmodium falciparum. Proceedings of the Royal Society of London B 268, 18551860.
Hughes A. L. and Verra F. (2002). Extensive polymorphism and ancient origin of Plasmodium falciparum. Trends in Parasitology 18, 348351.
Hughes A. L. and Verra F. (2010). Malaria parasite sequences from chimpanzee support the co-speciation hypothesis for the origin of virulent human malaria (Plasmodium falciparum). Molecular Phylogenetics and Evolution 57, 135143.
Hughes M. K. and Hughes A. L. (1995). Natural selection on Plasmodium surface proteins. Molecular and Biochemical Parasitology 71, 99113.
Jongwutiwes S., Putaporntip C., Iwasaki T., Ferreira M. U., Kanbara H. and Hughes A. L. (2005). Mitochondrial genome sequences support ancient population expansion in Plasmodium vivax. Molecular Biology and Evolution 22, 17331739.
Joy D. A., Feng X., Mu J., Furuya F., Chotivanich K., Krettli A. U., Ho M., Wang A., White N. J., Suh E., Beerli P., and Su X. (2003). Early origin and recent expansion of Plasmodium falciparum. Science 300, 318321.
Kappe S. H., Vaughn A. M., Boddey J. A. and Cowman A. F. (2010). That was then but this is now: malaria research in the time of an eradication agenda. Science 328, 862866.
Killick-Kendrick R. (1968). Malaria parasites of Thamnomys rutilans (Rodentia, Muridae) in Nigeria. Bulletin of the World Health Organization 38, 822824.
Krief S., Escalante A. A., Pacheco M. A., Mugisha L., Andre C., Halbwax M., Fischer A., Krief J. M., Kasenene J. M., Crandfield M., Cornejo O. E., Chavatte J. M., Lin C., Letourneur F., Gruner A. C., McCutchan T. F., Renia L. and Snounou G. (2010). On the diversity of malaria parasites in African apes and the origin of Plasmodium falciparum from Bonobos. PLoS Pathogens 6, e1000765.
Lefevre T., Sanchez M., Ponton F., Hughes D. and Thomas F. (2007). Virulence and resistance in malaria: who drives the outcome of the infection? Trends in Parasitology 23, 299302.
Li W. H. (1997). Molecular Evolution. Sinauer, Sunderland, MA.
Li W.-H. and Sadler L. A. (1991). Low nucleotide diversity in man. Genetics 129, 513523.
Liu W., Li Y., Learn G. H., Rudicell R. S., Robertson J. D., Keele B. F., Ndjango J.-B. N., Sanz C. M., Morgan D. B., Locatelli S., Gonder M. K., Kranzusch P. J., Walsh P. D., Delaporte E., Mpoudi-Ngole E., Georgiev A. V., Müller M. N., Shaw G. M., Peeters M., Sharp P. M., Rayner J. C. and Hahn B. H. (2010). Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467, 420425.
Livingstone F. B. (1958). Anthropological implications of sickle cell gene distribution in West Africa. American Anthropologist 60, 531561.
Martinsen E. S., Perkins S. L. and Schall J. J. (2008). A three-genome phylogeny of malaria parasites (Plasmodium and closely related genera): Evolution of life-history traits and host switches. Molecular Phylogenetics and Evolution 47, 261273.
McCutchan T. F., Kissinger J. C., Touray M. G., Rogers M. J., Li J., Sullivan M., Braga E. M., Krettli A. U. and Miller L. H. (1996). Comparison of circumsporozoite proteins from avian and mammalian malarias: biological and phylogenetic implications. Proceedings of the National Academy of Sciences, USA 93, 1188911894.
McIntosh M. T., Srivasta R. and Vaidya A. B. (1998). Divergent evolutionary constraints on mitochondrial and nuclear genomes of malaria parasites. Molecular and Biochemical Parasitology 95, 6980.
Miller M. A., Holder M. T., Vos R., Midford P. E., Liebowitz T., Chan L., Hoover P. and Warnow T. (2010). The CIPRES Portals. CIPRES. 2009-08-04. URL: Accessed: 2009-08-04. (Archived by WebCite(r) at
Mitsui H., Arisue N., Sakihama N., Inagaki Y., Horii T., Hasegawa M., Tanabe K. and Hashimoto T. (2010). Phylogeny of Asian primate malarias inferred from apicoplast genome-encoded genes with special emphasis on the positions of Plasmodium vivax and P. fragile. Gene 450, 3238.
Morgan D., Sanz C., Onononga J. R. and Strindberg S. (2006). Ape abundance and habitat use in the Gouaougo Triange, Republic of Congo. International Journal of Primatology 27, 147179.
Mu J., Duan J., Markova K., Joy D., Huynh C. Q., Branch O. H., Li W.-H. and Su X. (2002). Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature 418, 323326.
Mu J., Joy D. A., Duan J., Huang Y., Carlton J., Walker J., Barnwell J., Beerli P., Charleston M. A., Pybus O. G. and Su X. (2005). Host switch leads to emergence of Plasmodium vivax malaria in humans. Molecular Biology and Evolution 22, 16861693.
Nei M. and Gojobori T. (1986). Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Molecular Biology and Evolution 3, 418426.
Nei M. and Kumar S. (2000). Molecular Evolution and Phylogenetics. Oxford University Press, New York.
Ollomo B., Durand P., Prugnolle F., Douzery E., Arnathau C., Nkoge D., Leroy E. and Renaud F. (2009). A new malaria agent in African hominids. PLoS Pathogens 5, e1000446.
Perkins S. L. and Schall J. J. (2002). A molecular phylogeny of malarial parasites recovered from cytochrome b gene sequences. Journal of Parasitology 88, 972978.
Prugnolle F., Durand P., Neel C., Ollomo B., Ayala F. J., Arnathau C., Etienne L., Mpoudi-Ngole E., Nkoghe D., Leroy E., Delaporte E., Peeters M. and Renaud F. (2010). African great apes are natural hosts of multiple related malaria species, including Plasmodium falciparum. Proceedings of the National Academy of Sciences, USA 107, 14581463.
Putaporntip C., Jongwutiwes S., Thongaree S., Seethamchai S., Grynberg P. and Hughes A. L. (2010). Ecology of malaria parasites infection Southeast Asian macaques: evidence from cytochrome b sequences. Molecular Ecology 19, 34663476.
Qari S. H., Shi Y. P., Pieniazek N. J., Collins W. E. and Lal A. A. (1996). Phylogenetic relationship among the malaria parasites based on small subunit rRNA gene sequences: monophyletic nature of the human malaria parasite, Plasmodium falciparum. Molecular Phylogenetics and Evolution 6, 157165.
Rich S. M., Leendertz F. H., Xu G., LeBreton M., Djoko C. F., Aminake M. N., Takang E. E., Diffo J. L., Pike B. L., Rosenthal B. M., Formenty P., Boesch C., Ayala F. J. and Wolfe N. D. (2009). The origin of malignant malaria. Proceedings of the National Academy of Sciences, USA 196, 1490214907.
Ricklefs R. E. and Outlaw D. C. (2010). A molecular clock for malaria parasites. Science 329, 226229.
Ronquist F. and Huelsenbeck J. P. (2003). MrBayes 3: Bayesian phylogenetic inference under mixed models. Bioinformatics 19, 15721574.
Roy S. W. and Irimia M. (2008). Origins of human malaria: rare genomic changes and full mitochondrial genomes confirm the relationship of Plasmodium falciparum to other mammalian parasites but complicate the origins of Plasmodium vivax. Molecular Biology and Evolution 25, 11921198.
Sanderson M. J. (1997). A nonparametric approach to estimating divergence timescales in the absence of rate constancy. Molecular Biology and Evolution 15, 12181231.
Siddall M. E. and Barta J. R. (1992). Phylogeny of Plasmodium species: estimation and inference. Journal of Parasitology 78, 567568.
Sorhannus U. and Fox M. (1999). Synonymous and nonsynonymous substitution rates in diatoms: a comparison between chloroplast and nuclear genes. Journal of Molecular Evolution 48, 209212.
Stamatakis A. (2006). RAxML-VI-HPC: Maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics 22, 26882690.
Steiper M. E. and Young N. M. (2009). Primates (Primates) In The Timetree of Life (ed. Hedges S. B. and Kumar S.), pp. 482486. Oxford University Press, New York.
Struhsaker T. T. (1981). Forest and primate conservation in East Africa. African Journal of Ecology 19, 99114.
Tamura K., Dudley J., Nei M. and Kumar S. (2007). MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Molecular Biology and Evolution 24, 15961599.
Tamura K. and Nei M. (1993). Estimation of the numberof nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Molecular Biology and Evolution 10, 512526.
Tanabe K., Mita T., Jombart T., Eriksson A., Horibe S., Placpac N., Ranford-Cartwright L., Sawai H., Sakihama N., Ohmae S., Nakamura M., Ferreira M. U., Escalante A. A., Prugnolle F., Björkman A., Färnet A., Kaneko A., Horii T., Manica A., Kishino H. and Balloux F. (2010) Plasmodium falciparum accompanied the human expansion out of Africa. Current Biology 20, 17.
Takezaki N., Rzhetsky A. and Nei M. (1995). Phylogenetic test of the molecular clock and linearized trees. Molecular Biology and Evolution 12, 823833.
The International SNP Map Working Group. (2002). A map of human genome sequence variation containing 1·42 million single nucleotide polymorphisms. Nature 409, 928933.
Thompson J. D., Higgins D. G. and Gibson T. J. (1994). CLUSTAL W: improvement of the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Research 22, 46734680.
Volkman S. K., Sabeti P. C., DeCaprio D., Neafsey D. E., Schaffner S. F., Milner A. A. Jr., Daily J. P., Sarr O., Ndiaye D., Ndir O., Mboup S., Duraisingh M. T., Lukens A., Derr A., Stange-Thomann N., Waggoner S., Onofrio R., Ziaugra L., Mauceli E., Gnerre S., Jaffe D. B., Zainoun J., Wiegand R. C., Birren B. W., Hartl D. L., Galagan J. E., Lander E. S. and Wirth D. F. (2007). A genome-wide map of diversity in Plasmodium falciparum. Nature Genetics 39, 113119.
Warhurst D. C. (1999). Drug resistance in Plasmodium falciparum malaria. Infection 27, S55S58.
Waters A. P., Higgins D. G. and McCutchan T. F. (1991). Plasmodium falciparum appears to have arisen as a result of lateral transfer between avian and human hosts. Proceedings of the National Academy of Sciences, USA 88, 31403144.
Wilgenbusch J. C., Warren D. L. and Swofford D. L. (2004). AWTY: A system for graphical exploration of MCMC convergence in Bayesian phylogenetic inference.
Wolfe N. D., Dunavan C. P. and Diamond J. (2007). Origins of major human infectious diseases. Nature 447, 279283.
Yang Z. (2007) PAML 4: phylogenetic analysis by maximum likelihood. Molecular Biology and Evolution 24, 15861591.
Yang Z. and Nielsen R. (2000). Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Molecular Biology and Evolution 17, 3243.
Yoeli M. and Most H. (1964). A study of Plasmodium berghei in Thamnomys surdaster, and in other experimental hosts. American Journal of Tropical Medicine and Hygiene 13, 659663.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

  • ISSN: 0031-1820
  • EISSN: 1469-8161
  • URL: /core/journals/parasitology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
Type Description Title
Supplementary Materials

Silva supplementary material
Table S1.doc

 Word (38 KB)
38 KB
Supplementary Materials

Silva supplementary material
Figure S1.txt

 Word (124 KB)
124 KB
Supplementary Materials

Silva supplementary material
Table S2.txt

 Word (52 KB)
52 KB
Supplementary Materials

Silva supplementary material
Table S3.doc

 Word (45 KB)
45 KB


Full text views

Total number of HTML views: 1
Total number of PDF views: 32 *
Loading metrics...

Abstract views

Total abstract views: 1338 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 20th October 2017. This data will be updated every 24 hours.