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Schistosoma mansoni, a snail‐borne, blood fluke that infects humans, was introduced into the Americas from Africa during the Trans‐Atlantic slave trade. As this parasite shows strong specificity to the snail intermediate host, we expected that adaptation to South American Biomphalaria spp. snails would result in population bottlenecks and strong signatures of selection. We scored 475,081 single nucleotide variants in 143 S. mansoni from the Americas (Brazil, Guadeloupe and Puerto Rico) and Africa (Cameroon, Niger, Senegal, Tanzania, and Uganda), and used these data to ask: (i) Was there a population bottleneck during colonization? (ii) Can we identify signatures of selection associated with colonization? (iii) What were the source populations for colonizing parasites? We found a 2.4‐ to 2.9‐fold reduction in diversity and much slower decay in linkage disequilibrium (LD) in parasites from East to West Africa. However, we observed similar nuclear diversity and LD in West Africa and Brazil, suggesting no strong bottlenecks and limited barriers to colonization. We identified five genome regions showing selection in the Americas, compared with three in West Africa and none in East Africa, which we speculate may reflect adaptation during colonization. Finally, we infer that unsampled populations from central African regions between Benin and Angola, with contributions from Niger, are probably the major source(s) for Brazilian S. mansoni. The absence of a bottleneck suggests that this is a rare case of a serendipitous invasion, where S. mansoni parasites were pre‐adapted to the Americas and able to establish with relative ease. [ABSTRACT FROM AUTHOR]

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. It has been argued that drug resistance is unlikely to spread rapidly in helminth parasites infecting humans. This is based, at least in part, on the premise that resistance mutations are rare or absent within populations prior to treatment, and take a long time to reach appreciable frequencies because helminth parasite generation time is long. This argument is critically dependent on the starting frequency of resistance alleles–if high levels of "standing variation" for resistance are present prior to deployment of treatment, resistance may spread rapidly. We examined frequencies of oxamniquine resistance alleles present in Schistosoma mansoni from Africa and the Middle East where oxamniquine has seen minimal use. We found that oxamniquine resistance alleles are widespread in the Old World, ranging from 4.29% in the Middle East to 14.91% in East African parasite populations. Furthermore, we show that resistance alleles from West African and the Caribbean schistosomes share a common origin, suggesting that these alleles travelled to the New World with S. mansoni during the transatlantic slave trade. Together, these results demonstrate extensive standing variation for oxamniquine resistance. Our results have important implications for both drug treatment policies and drug development efforts, and demonstrate the power of molecular surveillance approaches for guiding helminth control. [ABSTRACT FROM AUTHOR]