Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

Steffen Borrmann; Judith Straimer; Leah Mwai; Abdirahman Abdi; Anja Rippert; John Okombo; Steven Muriithi; Philip Sasi; Moses Mosobo Kortok; Brett Lowe; Susana Campino; Samuel Assefa; Sarah Auburn; Magnus Manske; Gareth Maslen; Norbert Peshu; Dominic P. Kwiatkowski; Kevin Marsh; Alexis Nzila; Taane G. Clark

doi:10.1038/srep03318

Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

Steffen Borrmann^*, Judith Straimer, Leah Mwai, Abdirahman Abdi, Anja Rippert, John Okombo, Steven Muriithi, Philip Sasi, Moses Mosobo Kortok, Brett Lowe, Susana Campino, Samuel Assefa, Sarah Auburn, Magnus Manske, Gareth Maslen, Norbert Peshu, Dominic P. Kwiatkowski, Kevin Marsh, Alexis Nzila, Taane G. Clark

^*Corresponding author for this work

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

60 Scopus citations

Abstract

Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.

Original language	English
Article number	3318
Journal	Scientific Reports
Volume	3
DOIs	https://doi.org/10.1038/srep03318
State	Published - 2013

Bibliographical note

Funding Information:
We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

ASJC Scopus subject areas

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UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Borrmann, S., Straimer, J., Mwai, L., Abdi, A., Rippert, A., Okombo, J., Muriithi, S., Sasi, P., Kortok, M. M., Lowe, B., Campino, S., Assefa, S., Auburn, S., Manske, M., Maslen, G., Peshu, N., Kwiatkowski, D. P., Marsh, K., Nzila, A., & Clark, T. G. (2013). Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. Scientific Reports, 3, Article 3318. https://doi.org/10.1038/srep03318

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title = "Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya",

abstract = "Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.",

author = "Steffen Borrmann and Judith Straimer and Leah Mwai and Abdirahman Abdi and Anja Rippert and John Okombo and Steven Muriithi and Philip Sasi and Kortok, \{Moses Mosobo\} and Brett Lowe and Susana Campino and Samuel Assefa and Sarah Auburn and Magnus Manske and Gareth Maslen and Norbert Peshu and Kwiatkowski, \{Dominic P.\} and Kevin Marsh and Alexis Nzila and Clark, \{Taane G.\}",

note = "Funding Information: We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.",

year = "2013",

doi = "10.1038/srep03318",

language = "English",

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Borrmann, S, Straimer, J, Mwai, L, Abdi, A, Rippert, A, Okombo, J, Muriithi, S, Sasi, P, Kortok, MM, Lowe, B, Campino, S, Assefa, S, Auburn, S, Manske, M, Maslen, G, Peshu, N, Kwiatkowski, DP, Marsh, K, Nzila, A & Clark, TG 2013, 'Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya', Scientific Reports, vol. 3, 3318. https://doi.org/10.1038/srep03318

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T1 - Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

AU - Borrmann, Steffen

AU - Straimer, Judith

AU - Mwai, Leah

AU - Abdi, Abdirahman

AU - Rippert, Anja

AU - Okombo, John

AU - Muriithi, Steven

AU - Sasi, Philip

AU - Kortok, Moses Mosobo

AU - Lowe, Brett

AU - Campino, Susana

AU - Assefa, Samuel

AU - Auburn, Sarah

AU - Manske, Magnus

AU - Maslen, Gareth

AU - Peshu, Norbert

AU - Kwiatkowski, Dominic P.

AU - Marsh, Kevin

AU - Nzila, Alexis

AU - Clark, Taane G.

N1 - Funding Information: We thank Ines Petersen for helpful comments and Bronwyn MacInnis for assistance. This work is published with the permission of the Director of KEMRI. This work was supported by a German Research Foundation (DFG) grant to S.B. The funding source had no role in the design of the study; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

PY - 2013

Y1 - 2013

N2 - Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.

AB - Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.

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U2 - 10.1038/srep03318

DO - 10.1038/srep03318

M3 - Article

C2 - 24270944

AN - SCOPUS:84888882898

SN - 2045-2322

VL - 3

JO - Scientific Reports

JF - Scientific Reports

M1 - 3318

ER -

Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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