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Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment
Chevalier, Frédéric D Le Clec’h, Winka McDew-White, Marina Menon, Vinay Guzman, Meghan A Holloway, Stephen P Cao, Xiaohang Taylor, Alexander B Kinung'hi, Safari Gouvras, Anouk N
Chevalier, Frédéric D
Le Clec’h, Winka
McDew-White, Marina
Menon, Vinay
Guzman, Meghan A
Holloway, Stephen P
Cao, Xiaohang
Taylor, Alexander B
Kinung'hi, Safari
Gouvras, Anouk N
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2019-10-25
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2019-05-23
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mutation
Schistosoma mansoni
haplotypes
Africa
parasitic diseases
alleles
Schistosoma
deletion mutation
Schistosoma mansoni
haplotypes
Africa
parasitic diseases
alleles
Schistosoma
deletion mutation
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Abstract
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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Chevalier 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.1007881
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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. The attached file is the published version of the article.
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1553-7366
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1553-7374
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openAccess