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dc.contributor.authorChevalier, Frédéric D
dc.contributor.authorLe Clec’h, Winka
dc.contributor.authorMcDew-White, Marina
dc.contributor.authorMenon, Vinay
dc.contributor.authorGuzman, Meghan A
dc.contributor.authorHolloway, Stephen P
dc.contributor.authorCao, Xiaohang
dc.contributor.authorTaylor, Alexander B
dc.contributor.authorKinung'hi, Safari
dc.contributor.authorGouvras, Anouk N
dc.contributor.authorWebster, BL
dc.contributor.authorWebster, Joanne P
dc.contributor.authorEmery, AM
dc.contributor.authorRollinson, D
dc.contributor.authorGarba Djirmay, Amadou
dc.contributor.authorAl Mashikhi, Khalid M
dc.contributor.authorAl Yafae, Salem
dc.contributor.authorIdris, Mohamed A
dc.contributor.authorMoné, Hélène
dc.contributor.authorMouahid, Gabriel
dc.contributor.authorHart, P John
dc.contributor.authorLoVerde, Philip T
dc.contributor.authorAnderson, Timothy JC
dc.date.accessioned2022-07-01T14:17:38Z
dc.date.available2022-07-01T14:17:38Z
dc.date.issued2019-10-25
dc.date.submitted2019-05-23
dc.identifier.citationChevalier FD, Le Clec’h W, McDew-White M, Menon V, Guzman MA, Holloway SP, et al. (2019) Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment. PLoS Pathog 15(10): e1007881. https://doi.org/10.1371/journal.ppat.1007881en_US
dc.identifier.issn1553-7366
dc.identifier.doi10.1371/journal.ppat.1007881
dc.identifier.urihttp://hdl.handle.net/10141/623006
dc.description.abstractDo 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.en_US
dc.language.isoenen_US
dc.publisherPublic Library of Science (PLoS)en_US
dc.rightsopenAccessen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleOxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deploymenten_US
dc.typeJournal Articleen_US
dc.identifier.eissn1553-7374
dc.identifier.journalPLOS Pathogensen_US
dc.date.updated2022-06-17T15:54:54Z
dc.identifier.volume15en_US
dc.identifier.issue10en_US
dc.identifier.startpagee1007881-e1007881en_US
elements.import.authorChevalier, Frédéric D
elements.import.authorLe Clec’h, Winka
elements.import.authorMcDew-White, Marina
elements.import.authorMenon, Vinay
elements.import.authorGuzman, Meghan A
elements.import.authorHolloway, Stephen P
elements.import.authorCao, Xiaohang
elements.import.authorTaylor, Alexander B
elements.import.authorKinung'hi, Safari
elements.import.authorGouvras, Anouk N
elements.import.authorWebster, Bonnie L
elements.import.authorWebster, Joanne P
elements.import.authorEmery, Aidan M
elements.import.authorRollinson, David
elements.import.authorGarba Djirmay, Amadou
elements.import.authorAl Mashikhi, Khalid M
elements.import.authorAl Yafae, Salem
elements.import.authorIdris, Mohamed A
elements.import.authorMoné, Hélène
elements.import.authorMouahid, Gabriel
elements.import.authorHart, P John
elements.import.authorLoVerde, Philip T
elements.import.authorAnderson, Timothy JC
dc.description.nhmCopyright: © 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. The attached file is the published version of the article.en_US
dc.description.nhmNHM Repository
dc.subject.nhmmutationen_US
dc.subject.nhmSchistosoma mansonien_US
dc.subject.nhmhaplotypesen_US
dc.subject.nhmAfricaen_US
dc.subject.nhmparasitic diseasesen_US
dc.subject.nhmallelesen_US
dc.subject.nhmSchistosomaen_US
dc.subject.nhmdeletion mutationen_US
refterms.dateFOA2022-07-01T14:17:39Z


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