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 Kwiatkowski, Kevin Marsh, Alexis Nzila, Taane Clark

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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 (PFB0560wPFB0630cPFF0445w) 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 languageEnglish
Article number3318
Pages (from-to)1-10
Number of pages10
JournalScientific Reports
Volume3
DOIs
Publication statusPublished - 2013
Externally publishedYes

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dihydroartemisinin
Kenya
Plasmodium falciparum
Artemisinins
Genome
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 1
Antimalarials
Genetic Association Studies
Heat-Shock Proteins
Drug Resistance
Genes
Single Nucleotide Polymorphism
Parasites
Homeostasis
Public Health
Infection
artemisinine

Cite this

Borrmann, Steffen ; Straimer, Judith ; Mwai, Leah ; Abdi, Abdirahman ; Rippert, Anja ; Okombo, John ; Muriithi, Steven ; Sasi, Philip ; Kortok, Moses Mosobo ; Lowe, Brett ; Campino, Susana ; Assefa, Samuel ; Auburn, Sarah ; Manske, Magnus ; Maslen, Gareth ; Peshu, Norbert ; Kwiatkowski, Dominic ; Marsh, Kevin ; Nzila, Alexis ; Clark, Taane. / Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. In: Scientific Reports. 2013 ; Vol. 3. pp. 1-10.
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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 Dominic Kwiatkowski and Kevin Marsh and Alexis Nzila and Taane Clark",
year = "2013",
doi = "10.1038/srep03318",
language = "English",
volume = "3",
pages = "1--10",
journal = "Scientific Reports",
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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, D, Marsh, K, Nzila, A & Clark, T 2013, 'Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya', Scientific Reports, vol. 3, 3318, pp. 1-10. https://doi.org/10.1038/srep03318

Genome-wide screen identifies new candidate genes associated with artemisinin susceptibility in Plasmodium falciparum in Kenya. / Borrmann, Steffen; Straimer, Judith; Mwai, Leah; Abdi, Abdirahman; Rippert, Anja; Okombo, John; Muriithi, Steven; Sasi, Philip; Kortok, Moses Mosobo; Lowe, Brett; Campino, Susana; Assefa, Samuel; Auburn, Sarah; Manske, Magnus; Maslen, Gareth; Peshu, Norbert; Kwiatkowski, Dominic; Marsh, Kevin; Nzila, Alexis; Clark, Taane.

In: Scientific Reports, Vol. 3, 3318, 2013, p. 1-10.

Research output: Contribution to journalArticleResearchpeer-review

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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

AU - Marsh, Kevin

AU - Nzila, Alexis

AU - Clark, Taane

PY - 2013

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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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