TY - JOUR
T1 - Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment
AU - Chevalier, Frédéric D.
AU - Le Clec’h, Winka
AU - McDew-White, Marina
AU - Menon, Vinay
AU - Guzman, Meghan A.
AU - Holloway, Stephen P.
AU - Cao, Xiaohang
AU - Taylor, Alexander B.
AU - Kinung’hi, Safari
AU - Gouvras, Anouk N.
AU - Webster, Bonnie L.
AU - Webster, Joanne P.
AU - Emery, Aidan M.
AU - Rollinson, David
AU - Djirmay, Amadou Garba
AU - Al Mashikhi, Khalid M.
AU - Yafae, Salem Al
AU - Idris, Mohamed A.
AU - Moné, Hélène
AU - Mouahid, Gabriel
AU - John Hart, P.
AU - LoVerde, Philip T.
AU - Timothy, J. C.Anderson
N1 - Funding Information:
This study was supported by NIH grants [R01-AI097576 (T.J.C.A.), R21-AI096277 (T.J.C. A.), R01-AI133749 (T.J.C.A.), R01-AI115691 and P50-AI098507 (P.T.L./P.J.H.)], World Health Organization [HQNTD1206356 (P.T.L.)], by the National Center for Advancing Translational Sciences (CTSA/IIMS award no. UL1-TR001120), the UTHSCSA Presidents Collaborative Research Fund (P.T.L./P.J.H.) and the Robert A. Welch Foundation [AQ-1399 (P.J.H.)]. The molecular work at Texas Biomed was conducted in facilities constructed with support from Research Facilities Improvement Program Grant (C06-RR013556) from the National Center for Research Resources (NIH). The AT&T Genomics Computing Center supercomputing facilities were supported by the AT&T Foundation and the National Center for Research Resources Grant (S10-RR029392). The X-ray Crystallography Core Laboratory is a part of the Institutional Research Cores at the University of Texas Health Science Center at San Antonio supported by the Office of the Vice President for Research and the Mays Cancer Center (NIH P30-CA054174). W.L was supported by a Cowles fellowship from Texas Biomed. CONTRAST was funded by the European Commission (FP6 STREP contract no. 032203). SCORE (https://score.uga. edu/) activities were funded by the University of Georgia Research Foundation Inc. (prime award no. 50816, sub awards RR374-053/4785416 and RR374-053/4785426), which is funded by the Bill & Melinda Gates Foundation for SCORE projects. SCAN is funded with support from the Wellcome Trust (grant no. 104958/Z/14/Z). All the biological material from Oman was obtained thanks to the financial supports from the Ministry of Health in Oman, the Sultan Qaboos University (grant no. IG/ MED/MICR/00/01), the French Ministry of Foreign Affairs (French Embassy in Oman) (grants nos. 402419B, 402415K and 339660F), the CNRS-Sciences de la Vie (grants no. 01N92/0745/1 and 02N60/1340), the CNRS-Direction des Relations internationales (grants no. 01N92/0745 and 02N60/1340, and the PICS-CNRS no. 06249: FRANC-INCENSE), the University of Perpignan and the National Institute of Health (NIH) (grant no. R01-AI133749 T.J.C.A.; Subaward no. 53409 H. M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Chevalier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019
Y1 - 2019
N2 - Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p. E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.
AB - Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p. E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni.
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U2 - 10.1371/journal.ppat.1007881
DO - 10.1371/journal.ppat.1007881
M3 - Article
C2 - 31652296
AN - SCOPUS:85074675822
SN - 1553-7366
VL - 15
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 10
M1 - e1007881
ER -