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; Pascal Ringwald; Frédéric Ariey; Christiane Dolecek; Tran Tinh Hien; Maciej F. Boni; Cao Quang Thai; Alfred Amambua-Ngwa; David J. Conway; Abdoulaye A. Djimdé; Ogobara K. Doumbo; Issaka Zongo; Jean Bosco Ouedraogo; Daniel Alcock; Eleanor Drury; Sarah Auburn; Oliver Koch; Mandy Sanders; Christina Hubbart; Gareth Maslen; Valentin Ruano-Rubio; Dushyanth Jyothi; Alistair Miles; John O'Brien; Chris Gamble; Samuel O. Oyola; Julian C. Rayner; Chris I. Newbold; Matthew Berriman; Chris C.A. Spencer; Gilean McVean; Nicholas P. Day; Nicholas J. White; Delia Bethell; Arjen M. Dondorp; Christopher V. Plowe; Rick M. Fairhurst; Dominic P. Kwiatkowski

doi:10.1038/ng.2624

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. HodgsonVictor Asoala, Mallika Imwong, Shannon Takala-Harrison, François Nosten, Xin Zhuan Su, Pascal Ringwald, Frédéric Ariey, Christiane Dolecek, Tran Tinh Hien, Maciej F. Boni, Cao Quang Thai, Alfred Amambua-Ngwa, David J. Conway, Abdoulaye A. Djimdé, Ogobara K. Doumbo, Issaka Zongo, Jean Bosco Ouedraogo, Daniel Alcock, Eleanor Drury, Sarah Auburn, Oliver Koch, Mandy Sanders, Christina Hubbart, Gareth Maslen, Valentin Ruano-Rubio, Dushyanth Jyothi, Alistair Miles, John O'Brien, Chris Gamble, Samuel O. Oyola, Julian C. Rayner, Chris I. Newbold, Matthew Berriman, Chris C.A. Spencer, Gilean McVean, Nicholas P. Day, Nicholas J. White, Delia Bethell, Arjen M. Dondorp, Christopher V. Plowe, Rick M. Fairhurst, Dominic P. Kwiatkowski^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

357 Scopus citations

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.

Original language	English
Pages (from-to)	648-655
Number of pages	8
Journal	Nature Genetics
Volume	45
Issue number	6
DOIs	https://doi.org/10.1038/ng.2624
State	Published - Jun 2013
Externally published	Yes

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Miotto, O., Almagro-Garcia, J., Manske, M., MacInnis, B., Campino, S., Rockett, K. A., Amaratunga, C., Lim, P., Suon, S., Sreng, S., Anderson, J. M., Duong, S., Nguon, C., Chuor, C. M., Saunders, D., Se, Y., Lon, C., Fukuda, M. M., Amenga-Etego, L., ... Kwiatkowski, D. P. (2013). Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia. Nature Genetics, 45(6), 648-655. https://doi.org/10.1038/ng.2624

@article{2f32e05386894f51bdcd51e4a72d8992,

title = "Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia",

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.",

author = "Olivo Miotto and Jacob Almagro-Garcia and Magnus Manske and Bronwyn MacInnis and Susana Campino and Rockett, {Kirk A.} and Chanaki Amaratunga and Pharath Lim and Seila Suon and Sokunthea Sreng and Anderson, {Jennifer M.} and Socheat Duong and Chea Nguon and Chuor, {Char Meng} and David Saunders and Youry Se and Chantap Lon and Fukuda, {Mark M.} and Lucas Amenga-Etego and Hodgson, {Abraham V.O.} and Victor Asoala and Mallika Imwong and Shannon Takala-Harrison and Fran{\c c}ois Nosten and Su, {Xin Zhuan} and Pascal Ringwald and Fr{\'e}d{\'e}ric Ariey and Christiane Dolecek and Hien, {Tran Tinh} and Boni, {Maciej F.} and Thai, {Cao Quang} and Alfred Amambua-Ngwa and Conway, {David J.} and Djimd{\'e}, {Abdoulaye A.} and Doumbo, {Ogobara K.} and Issaka Zongo and Ouedraogo, {Jean Bosco} and Daniel Alcock and Eleanor Drury and Sarah Auburn and Oliver Koch and Mandy Sanders and Christina Hubbart and Gareth Maslen and Valentin Ruano-Rubio and Dushyanth Jyothi and Alistair Miles and John O'Brien and Chris Gamble and Oyola, {Samuel O.} and Rayner, {Julian C.} and Newbold, {Chris I.} and Matthew Berriman and Spencer, {Chris C.A.} and Gilean McVean and Day, {Nicholas P.} and White, {Nicholas J.} and Delia Bethell and Dondorp, {Arjen M.} and Plowe, {Christopher V.} and Fairhurst, {Rick M.} and Kwiatkowski, {Dominic P.}",

note = "Funding Information: We would like to thank V. Cornelius and R. Giacomantonio for their support in producing and reviewing this manuscript; S. Uk and E.S. Phelps for their contributions in the Cambodian studies; and T. Anderson for helpful review comments. The sequencing, genotyping and analysis components of this study were supported by the Wellcome Trust through core funding of the Wellcome Trust Sanger Institute (098051), core funding of the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z) and a Strategic Award (090770/Z/09/Z) and the MRC through the MRC Centre for Genomics and Global Health (G0600718) and an MRC Professorship to D.P.K. (G19/9). Other parts of this study were partly supported by the Wellcome Trust; the MRC; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and a Howard Hughes Medical Institute International Scholarship (55005502) to A.A.D. P.R. is a staff member of the World Health Organization; he alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of the World Health Organization.",

year = "2013",

month = jun,

doi = "10.1038/ng.2624",

language = "English",

volume = "45",

pages = "648--655",

journal = "Nature Genetics",

issn = "1061-4036",

number = "6",

}

Miotto, O, Almagro-Garcia, J, Manske, M, MacInnis, B, Campino, S, Rockett, KA, Amaratunga, C, Lim, P, Suon, S, Sreng, S, Anderson, JM, Duong, S, Nguon, C, Chuor, CM, Saunders, D, Se, Y, Lon, C, Fukuda, MM, Amenga-Etego, L, Hodgson, AVO, Asoala, V, Imwong, M, Takala-Harrison, S, Nosten, F, Su, XZ, Ringwald, P, Ariey, F, Dolecek, C, Hien, TT, Boni, MF, Thai, CQ, Amambua-Ngwa, A, Conway, DJ, Djimdé, AA, Doumbo, OK, Zongo, I, Ouedraogo, JB, Alcock, D, Drury, E, Auburn, S, Koch, O, Sanders, M, Hubbart, C, Maslen, G, Ruano-Rubio, V, Jyothi, D, Miles, A, O'Brien, J, Gamble, C, Oyola, SO, Rayner, JC, Newbold, CI, Berriman, M, Spencer, CCA, McVean, G, Day, NP, White, NJ, Bethell, D, Dondorp, AM, Plowe, CV, Fairhurst, RM & Kwiatkowski, DP 2013, 'Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia', Nature Genetics, vol. 45, no. 6, pp. 648-655. https://doi.org/10.1038/ng.2624

TY - JOUR

T1 - Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

AU - Miotto, Olivo

AU - Almagro-Garcia, Jacob

AU - Manske, Magnus

AU - MacInnis, Bronwyn

AU - Campino, Susana

AU - Rockett, Kirk A.

AU - Amaratunga, Chanaki

AU - Lim, Pharath

AU - Suon, Seila

AU - Sreng, Sokunthea

AU - Anderson, Jennifer M.

AU - Duong, Socheat

AU - Nguon, Chea

AU - Chuor, Char Meng

AU - Saunders, David

AU - Se, Youry

AU - Lon, Chantap

AU - Fukuda, Mark M.

AU - Amenga-Etego, Lucas

AU - Hodgson, Abraham V.O.

AU - Asoala, Victor

AU - Imwong, Mallika

AU - Takala-Harrison, Shannon

AU - Nosten, François

AU - Su, Xin Zhuan

AU - Ringwald, Pascal

AU - Ariey, Frédéric

AU - Dolecek, Christiane

AU - Hien, Tran Tinh

AU - Boni, Maciej F.

AU - Thai, Cao Quang

AU - Amambua-Ngwa, Alfred

AU - Conway, David J.

AU - Djimdé, Abdoulaye A.

AU - Doumbo, Ogobara K.

AU - Zongo, Issaka

AU - Ouedraogo, Jean Bosco

AU - Alcock, Daniel

AU - Drury, Eleanor

AU - Auburn, Sarah

AU - Koch, Oliver

AU - Sanders, Mandy

AU - Hubbart, Christina

AU - Maslen, Gareth

AU - Ruano-Rubio, Valentin

AU - Jyothi, Dushyanth

AU - Miles, Alistair

AU - O'Brien, John

AU - Gamble, Chris

AU - Oyola, Samuel O.

AU - Rayner, Julian C.

AU - Newbold, Chris I.

AU - Berriman, Matthew

AU - Spencer, Chris C.A.

AU - McVean, Gilean

AU - Day, Nicholas P.

AU - White, Nicholas J.

AU - Bethell, Delia

AU - Dondorp, Arjen M.

AU - Plowe, Christopher V.

AU - Fairhurst, Rick M.

AU - Kwiatkowski, Dominic P.

N1 - Funding Information: We would like to thank V. Cornelius and R. Giacomantonio for their support in producing and reviewing this manuscript; S. Uk and E.S. Phelps for their contributions in the Cambodian studies; and T. Anderson for helpful review comments. The sequencing, genotyping and analysis components of this study were supported by the Wellcome Trust through core funding of the Wellcome Trust Sanger Institute (098051), core funding of the Wellcome Trust Centre for Human Genetics (090532/Z/09/Z) and a Strategic Award (090770/Z/09/Z) and the MRC through the MRC Centre for Genomics and Global Health (G0600718) and an MRC Professorship to D.P.K. (G19/9). Other parts of this study were partly supported by the Wellcome Trust; the MRC; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, US National Institutes of Health; and a Howard Hughes Medical Institute International Scholarship (55005502) to A.A.D. P.R. is a staff member of the World Health Organization; he alone is responsible for the views expressed in this publication, and they do not necessarily represent the decisions, policy or views of the World Health Organization.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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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U2 - 10.1038/ng.2624

DO - 10.1038/ng.2624

M3 - Article

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AN - SCOPUS:84878715473

SN - 1061-4036

VL - 45

SP - 648

EP - 655

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Multiple populations of artemisinin-resistant Plasmodium falciparum in Cambodia

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