Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni
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Mass-drug administration (MDA) of human populations using praziquantel monotherapy has become the primary strategy for controlling and potentially eliminating the major neglected tropical disease schistosomiasis. To understand how long-term MDA impacts schistosome populations, we analysed whole-genome sequence data of 570 Schistosoma mansoni samples (and the closely related outgroup species, S. rodhaini) from eight countries incorporating both publicly-available sequence data and new parasite material. This revealed broad-scale genetic structure across countries but with extensive transmission over hundreds of kilometres. We characterised variation across the transient receptor potential melastatin ion channel, TRPMPZQ, a target of praziquantel, which has recently been found to influence praziquantel susceptibility. Functional profiling of TRPMPZQ variants found in endemic populations identified four mutations that reduced channel sensitivity to praziquantel, indicating standing variation for resistance. Analysis of parasite infrapopulations sampled from individuals pre- and post-treatment identified instances of treatment failure, further indicative of potential praziquantel resistance. As schistosomiasis is targeted for elimination as a public health problem by 2030 in all currently endemic countries, and even interruption of transmission in selected African regions, we provide an in-depth genomic characterisation of endemic populations and an approach to identify emerging praziquantel resistance alleles.
Extensive transmission and variation in a functional receptor for praziquantel resistance in endemic Schistosoma mansoni.
Duncan J. Berger, Sang-Kyu Park, Thomas Crellen, Tushabe John Vianney, Narcis B. Kabatereine, James A. Cotton, Richard Sanya, Alison Elliot, Edridah M. Tukahebwa, Moses Adriko, Claire J. Standley, Anouk Gouvras, Safari Kinung’hi, Helmut Haas, Muriel Rabone, Aidan Emery, Poppy H. L. Lamberton, Bonnie L. Webster, Fiona Allan, Sarah Buddenborg, Matthew Berriman, Jonathan S. Marchant, Stephen R. Doyle, Joanne P. Webster. bioRxiv 2024.08.29.610291. https://doi.org/10.1101/2024.08.29.610291.
The sequencing data generated in this study have been deposited in the European Nucleotide Archive (ENA) repository under project accession codes: PRJEB42451, PRJEB29904.