Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Frédéric D. Chevalier, Winka Le Clec’h, Marina McDew-White, Vinay Menon, Meghan A. Guzman, Stephen P. Holloway, Xiaohang Cao, Alexander B. Taylor, Safari Kinung’hi, Anouk N. Gouvras, Bonnie L. Webster, Joanne P. Webster, Aidan M. Emery, David Rollinson, Amadou Garba Djirmay, Khalid M. Al Mashikhi, Salem Al Yafae, Mohamed A. Idris, Hélène Moné, Gabriel MouahidP. John Hart, Philip T. LoVerde, J. C.Anderson Timothy

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Article numbere1007881
JournalPLoS Pathogens
Volume15
Issue number10
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Chevalier, F. D., Le Clec’h, W., McDew-White, M., Menon, V., Guzman, M. A., Holloway, S. P., Cao, X., Taylor, A. B., Kinung’hi, S., Gouvras, A. N., Webster, B. L., Webster, J. P., Emery, A. M., Rollinson, D., Djirmay, A. G., Al Mashikhi, K. M., Yafae, S. A., Idris, M. A., Moné, H., ... Timothy, J. C. A. (2019). Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment. PLoS Pathogens, 15(10), [e1007881]. https://doi.org/10.1371/journal.ppat.1007881