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Multiple populations of artemisinin resistant plasmodium falciparum in cambodia nature genetics - nature publishing group
1. 30/04/13 Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia : Nature Genetics : Nature Publishing Group
www.nature.com/ng/journal/vaop/ncurrent/pdf/ng.2624.pdf 1/4
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Multiple populations of artemisinin-resistant Plasmodium
falciparum in Cambodia
Olivo Miotto, Jacob Almagro-Garcia, Magnus Manske, Bronwyn MacInnis, Susana Campino, Kirk A Rockett, Chanaki
Amaratunga, Pharath Lim, Seila Suon, Sokunthea Sreng, Jennifer M Anderson, Socheat Duong, Chea Nguon, Char
Meng Chuor, David Saunders, Youry Se, Chantap Lon, Mark M Fukuda, Lucas Amenga-Etego, Abraham V O
Hodgson, Victor Asoala, Mallika Imwong, Shannon Takala-Harrison, François Nosten, Xin-zhuan Su et al.
Nature Genetics (2013) doi:10.1038/ng.2624
Received 30 November 2012 Accepted 04 April 2013 Published online 28 April 2013
Abstract
We describe an analysis of genome variation in 825 P. falciparum samples from Asia and Africa that identifies an unusual pattern
of parasite population structure at the epicenter of artemisinin resistance in western Cambodia. Within this relatively small
geographic area, we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high
levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to
artemisinin, which have skewed allele frequency spectra and high levels of haplotype homozygosity, indicative of founder effects
and recent population expansion. We provide a catalog of SNPs that show high levels of differentiation in the artemisinin-
resistant subpopulations, including codon variants in transporter proteins and DNA mismatch repair proteins. These data provide
a population-level genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular
markers to assist in its elimination.
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Affiliations
Medical Research Council (MRC) Centre for Genomics and Global Health, University of Oxford, Oxford, UK.
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2. 30/04/13 Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia : Nature Genetics : Nature Publishing Group
www.nature.com/ng/journal/vaop/ncurrent/pdf/ng.2624.pdf 2/4
Olivo Miotto, Jacob Almagro-Garcia, Kirk A Rockett, Lucas Amenga-Etego, Oliver Koch, Alistair Miles, Chris I Newbold, Chris C A
Spencer & Dominic P Kwiatkowski
Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
Olivo Miotto, Mallika Imwong, François Nosten, Nicholas P Day, Nicholas J White & Arjen M Dondorp
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Olivo Miotto, Jacob Almagro-Garcia, Magnus Manske, Bronwyn MacInnis, Susana Campino, Kirk A Rockett, Daniel Alcock,
Eleanor Drury, Mandy Sanders, Gareth Maslen, Valentin Ruano-Rubio, Dushyanth Jyothi, Samuel O Oyola, Julian C Rayner,
Chris I Newbold, Matthew Berriman & Dominic P Kwiatkowski
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Jacob Almagro-Garcia, Kirk A Rockett, Christina Hubbart, Valentin Ruano-Rubio, Alistair Miles, John O'Brien, Chris C A Spencer,
Gilean McVean & Dominic P Kwiatkowski
National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
Chanaki Amaratunga, Pharath Lim, Jennifer M Anderson, Xin-zhuan Su & Rick M Fairhurst
National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
Pharath Lim, Seila Suon, Sokunthea Sreng, Socheat Duong, Chea Nguon & Char Meng Chuor
Department of Immunology and Medicine, US Army Medical Component, Armed Forces Research Institute of
Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand.
David Saunders, Mark M Fukuda & Delia Bethell
USAMC-AFRIMS, Phnom Penh, Cambodia.
Youry Se & Chantap Lon
Armed Forces Health Surveillance Center, Silver Spring, Maryland, USA.
Mark M Fukuda
Navrongo Health Research Centre, Navrongo, Ghana.
Lucas Amenga-Etego, Abraham V O Hodgson & Victor Asoala
Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University,
Bangkok, Thailand.
Mallika Imwong
Howard Hughes Medical Institute, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Shannon Takala-Harrison & Christopher V Plowe
Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand.
François Nosten
Centre for Tropical Medicine, University of Oxford, Oxford, UK.
François Nosten, Christiane Dolecek, Tran Tinh Hien, Maciej F Boni, Nicholas P Day, Nicholas J White & Arjen M Dondorp
Global Malaria Programme, World Health Organization, Geneva, Switzerland.
Pascal Ringwald
Unité d'Immunologie Moléculaire des Parasites, Institut Pasteur, Paris, France.
Frédéric Ariey
Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam.
Christiane Dolecek, Tran Tinh Hien, Maciej F Boni & Cao Quang Thai
3. 30/04/13 Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia : Nature Genetics : Nature Publishing Group
www.nature.com/ng/journal/vaop/ncurrent/pdf/ng.2624.pdf 3/4
MRC Laboratories, Fajara, The Gambia.
Alfred Amambua-Ngwa & David J Conway
London School of Hygiene and Tropical Medicine, London, UK.
David J Conway
Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies of
Bamako, Bamako, Mali.
Abdoulaye A Djimdé & Ogobara K Doumbo
Institut de Recherche en Sciences de la Santé, Direction Régionale de l'Ouést, Bobo-Dioulasso, Burkina Faso.
Issaka Zongo & Jean-Bosco Ouedraogo
Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
Sarah Auburn
Department of Statistics, University of Oxford, Oxford, UK.
Chris Gamble
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Chris I Newbold
Deceased.
Youry Se
Contributions
S.C., C.A., P.L., S. Suon, S. Sreng, J.M.A., S.D., C.N., C.M.C., D.S., Y.S., C.L., M.M.F., L.A.-E., A.V.O.H., V.A., M.I., F.N., X.S.,
P.R., F.A., C.D., T.T.H., M.F.B., C.Q.T., A.A.-N., D.J.C., A.A.D., O.K.D., I.Z., J.-B.O., S.A., N.P.D., N.J.W., D.B., A.M.D., C.V.P. and
R.M.F. carried out field and laboratory studies to obtain P. falciparum samples for sequencing. C.A., P.L., S. Suon, S. Sreng,
J.M.A., S.D., C.N., C.M.C., D.S., Y.S., C.L., M.M.F., F.N., X.S., P.R., F.A., N.J.W., D.B., A.M.D., C.V.P. and R.M.F. carried out
clinical studies to obtain ART phenotype data. S.C., D.A., E.D., M.S., S.A., O.K., S.O.O., B.M., C.I.N. and M.B. developed and
implemented methods for sample processing and sequencing library preparation. O.M., J.A.-G., M.M., G. Maslen, V.R.-R., D.J.
and A.M. developed software for data management and visualization. K.A.R., C.H., D.A. and M.M. carried out validation
experiments. C.V.P., S.T.-H., G. McVean and R.M.F. contributed to development of the project. B.M., M.B., C.I.N. and J.C.R.
provided project management and oversight. O.M., J.A.-G., M.M., J.O., C.G. and C.C.A.S. carried out data analyses. D.P.K.,
O.M. and J.A.-G. wrote the manuscript. All authors reviewed the manuscript.
Competing financial interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to: Dominic P Kwiatkowski
Supplementary information
PDF files
1. Supplementary Text and Figures (2 MB)
Supplementary Figures 1–9, Supplementary Tables 1–6 and 8–14, Supplementary Note
Excel files
1. Supplementary Table 7 (143 KB)
Lists of SNPs that are highly differentiated in the Cambodian outlier subpopulations, compared to KH1.