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

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

doi:10.1371/journal.ppat.1007881

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.

Highlights

The rate at which drug resistance alleles spread within populations in response to a drug treatment is critically dependent on the starting frequency of resistance alleles in the population when new drugs are deployed [1,2]
It has been argued that drug resistance is unlikely to spread rapidly in helminth parasites infecting humans
We examined frequencies of oxamniquine resistance alleles present in Schistosoma mansoni from Africa and the Middle East where oxamniquine has seen minimal use

Summary

Introduction

The rate at which drug resistance alleles (or any other beneficial alleles) spread within populations in response to a drug treatment (or any other selection pressure) is critically dependent on the starting frequency of resistance alleles in the population when new drugs are deployed [1,2] If no such alleles are present when a novel drug is introduced, there is a waiting time for resistance alleles to arise. The barrier to establishment is severe for recessive traits because these will be present in heterozygotes at low frequency and not exposed to selection This effect, otherwise known as “Haldane’s sieve” [4], may be relevant for drug resistance evolution in diploid pathogens, because resistance mutations in drug targets typically result in phenotypic resistance only when two copies are present.

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