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Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

Nature Genetics volume 42, pages 268–271 (2010)Cite this article

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Abstract

Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome1,2; screening for genes under selection may suggest potential drug or immune targets3. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of ∼1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome.

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Figure 1: Population structure and principal component analysis (PCA) of Plasmodium falciparum parasite populations.
Figure 2: Loci subject to positive selection in P. falciparum populations from Africa, Asia and America.
Figure 3: In vitro parasite responses (IC50) to seven antimalarial drugs.
Figure 4: Genome-wide scan for SNPs associated with responses to antimalarial drugs in the Asian population.

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Acknowledgements

This work was supported by the Division of Intramural Research, NIAID, NIH (USA), funds from the Canadian Institute of Health Research #11284 and #200183, the US National Academies Keck Genome Initiative, and the Human Frontiers in Science Program #RGP54/2006 for P.A. K.C. and N.J.W. are supported by the Wellcome Trust. S.L. was supported by the 973 National Basic Research Program of China, #2007CB513103. We also thank J. Sattabongkot for help in parasite shipping, J. Dunn and L. Zhang for assistance in parasite culture and NIAID intramural editor B.R. Marshall for assistance.

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Authors and Affiliations

  1. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA

    Jianbing Mu, Hongying Jiang, Shengfa Liu, Rick M Fairhurst, Thomas E Wellems & Xin-zhuan Su

  2. Department of Pediatrics, University of Montreal, Faculty of Medicine, Sainte Justine Research Centre, Montreal, Quebec, Canada

    Rachel A Myers & Philip Awadalla

  3. Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA

    Rachel A Myers

  4. School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Shengfa Liu

  5. Genomics Unit, Research Technologies Section, Research Technologies Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, USA

    Stacy Ricklefs, Daniel E Sturdevant & Stephen F Porcella

  6. Laboratory of Immunogenetics, NIAID, NIH, Bethesda, Maryland, USA

    Michael Waisberg

  7. Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    Kesinee Chotivanich & Polrat Wilairatana

  8. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    Srivicha Krudsood

  9. Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme, Mahidol University, Bangkok, Thailand

    Nicholas J White

  10. Pathobiology Department, Faculty of Science, Mahidol University, Bangkok, Thailand

    Rachanee Udomsangpetch

  11. Department of Entomology, Pennsylvania State University, University Park, Pennsylvania, USA

    Liwang Cui

  12. Department of Microbiology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada

    May Ho

  13. Research Center for Qinghao, Guangzhou, China

    Fengzhen Ou, Haibo Li, Jianping Song & Guoqiao Li

  14. Guangzhou University of Chinese Medicine, Guangzhou, China

    Xinhua Wang

  15. National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia

    Suon Seila, Sreng Sokunthea & Duong Socheat

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  1. Jianbing Mu
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Correspondence to Jianbing Mu, Philip Awadalla or Xin-zhuan Su.

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Mu, J., Myers, R., Jiang, H. et al. Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs. Nat Genet 42, 268–271 (2010). https://doi.org/10.1038/ng.528

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