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A genome-wide map of diversity in Plasmodium falciparum

Nature Genetics volume 39, pages 113–119 (2007)Cite this article

Abstract

Genetic variation allows the malaria parasite Plasmodium falciparum to overcome chemotherapeutic agents, vaccines and vector control strategies and remain a leading cause of global morbidity and mortality1. Here we describe an initial survey of genetic variation across the P. falciparum genome. We performed extensive sequencing of 16 geographically diverse parasites and identified 46,937 SNPs, demonstrating rich diversity among P. falciparum parasites (π = 1.16 × 10−3) and strong correlation with gene function. We identified multiple regions with signatures of selective sweeps in drug-resistant parasites, including a previously unidentified 160-kb region with extremely low polymorphism in pyrimethamine-resistant parasites. We further characterized 54 worldwide isolates by genotyping SNPs across 20 genomic regions. These data begin to define population structure among African, Asian and American groups and illustrate the degree of linkage disequilibrium, which extends over relatively short distances in African parasites but over longer distances in Asian parasites. We provide an initial map of genetic diversity in P. falciparum and demonstrate its potential utility in identifying genes subject to recent natural selection and in understanding the population genetics of this parasite.

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Figure 1: Geographic distribution of parasites and SNPs.
Figure 2: Genetic diversity within Gene Ontology (GO) functional categories.
Figure 3: Nucleotide diversity identifies potential selective sweeps.
Figure 4: Patterns of linkage disequilibrium at 20 loci distributed across the P. falciparum genome in Asian and African parasites.

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Acknowledgements

We thank all members of the sample collection team in Senegal (A. Ahouidi, L. Ndiaye, O. Ly, Y. Diedhiou, T. Sene, A. Mbaye and D. Diop). We thank T. Taylor, K. Seydel, J. Montgomery, E. Dembo, M. Molyneux and S. Rogerson for help collecting the samples from Malawi. We also thank all the members of the Broad Sequencing Platform and M. Koehrsen, D. Richter and O. Shamovsky for sequence analysis help. Our thanks to M. Goyette and T. Rachupka for help with Sequenom genotyping. Thanks to N. Mahesh and G. Ramirez for help with sample preparation and parasite cultures and to J. Mu and X. Su for typing samples. We thank MR4 for providing us with malaria parasites contributed by the following depositors: W.E. Collins (MRA-347); D.E. Kyle (MRA-154, MRA-157, MRA-159, MRA-176, MRA-207, MRA-284, MRA-285); L.H. Miller and D. Baruch (MRA-331, MRA-326, MRA-328); W. Trager (MRA-731, MRA-732, MRA-733); D. Walliker (MRA-151, MRA-153, MRA-200); T.E. Wellems (MRA-155, MRA-156, MRA-309, MRA-464); and Y. Wu (MRA-201). Special thanks to J. Barnwell for providing P. reichenowi DNA. Our thanks to PlasmoDB (http://www.plasmodb.org) for access to the 3D7 genome sequence. The authors are supported by the US National Institutes of Health, SPARC funding of The Broad Institute of MIT and Harvard, the Burroughs-Wellcome Fund, The Bill and Melinda Gates Foundation, the NIAID Microbial Sequencing Center, the Ellison Medical Foundation, Fogarty International and the Exxon Mobil Foundation. P.C.S. is funded by the Damon Runyon Cancer Fellowship and the L'Oreal for Women in Science Award.

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Author notes

  1. Sarah K Volkman and Pardis C Sabeti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Sarah K Volkman, Danny A Milner Jr, Johanna P Daily, Manoj T Duraisingh, Amanda Lukens & Dyann F Wirth

  2. The Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, USA

    Pardis C Sabeti, David DeCaprio, Daniel E Neafsey, Stephen F Schaffner, Alan Derr, Nicole Stange-Thomann, Skye Waggoner, Robert Onofrio, Liuda Ziaugra, Evan Mauceli, Sante Gnerre, David B Jaffe, Joanne Zainoun, Roger C Wiegand, Bruce W Birren, James E Galagan, Eric S Lander & Dyann F Wirth

  3. Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, BP 7325, Senegal

    Ousmane Sarr, Daouda Ndiaye, Omar Ndir & Soulyemane Mboup

  4. Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Daniel L Hartl

  5. Department of Biology, MIT, Cambridge, 02139, Massachusetts, USA

    Eric S Lander

  6. Whitehead Institute for Biomedical Research, Cambridge, 02142, Massachusetts, USA

    Eric S Lander

  7. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Eric S Lander

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  1. Sarah K Volkman
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Contributions

S.K.V. designed experiments, prepared samples, carried out Sequenom genotyping and PCR resequencing, analyzed genotyping data and wrote the paper. P.C.S. designed experiments; carried out Sequenom genotyping and PCR resequencing; analyzed data for linkage disequilibrium, allele frequency and long-range haplotypes and wrote the paper. D.D.C. analyzed sequence data, prepared sequence data for subsequent analysis and defined polymorphisms. D.E.N. analyzed data for allele frequency and nucleotide diversity by GO category. S.F.S. analyzed data for nucleotide diversity and selective sweeps. D.A.M., J.P.D., O.S., D.N., O.N., S.M. and M.T.D. helped with sample collection. J.P.D. and M.T.D. helped with culture adaptation. D.A.M. and A.L. helped with parasite cultures. A.D. helped with GO function analysis. N.S.-T. and J.Z. prepared libraries for sequencing. S.W. and R.O. helped with PCR resequencing. L.Z. helped with Sequenom genotyping. E.M., S.G. and D.B.J. created the genome assemblies for HB3 and Dd2. R.C.W. coordinated project flow. B.W.B. supervised sequencing. D.L.H. consulted on population genetic analysis. J.E.G. supervised and advised on sequence analysis. E.S.L. designed experiments, consulted on project outcomes and wrote the paper. D.F.W. designed experiments, coordinated all efforts, supervised project at all levels, consulted on project outcomes and wrote the paper.

Corresponding author

Correspondence to Dyann F Wirth.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Sample correspondence for SNPs. (PDF 408 kb)

Supplementary Fig. 2

Separation of continental populations using genotyping SNPs. (PDF 396 kb)

Supplementary Fig. 3

Allele frequency in spectra. (PDF 207 kb)

Supplementary Table 1

Parasites used in the study. (PDF 427 kb)

Supplementary Table 2

Twenty chromosomal regions selected for LD study. (PDF 264 kb)

Supplementary Table 3

Nucleotide diversity across the genome. (PDF 258 kb)

Supplementary Table 4

Comparison of genotyping from whole genome–amplified samples and the original unamplified sample. (PDF 243 kb)

Supplementary Methods (PDF 276 kb)

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Volkman, S., Sabeti, P., DeCaprio, D. et al. A genome-wide map of diversity in Plasmodium falciparum. Nat Genet 39, 113–119 (2007). https://doi.org/10.1038/ng1930

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