{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:55:42Z","timestamp":1793087742383,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011081","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000}}],"reference-count":117,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/1002480\/1"],"award-info":[{"award-number":["BB\/1002480\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/P001912\/1"],"award-info":[{"award-number":["BB\/P001912\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Fasciola hepatica<\/jats:italic>infection is responsible for substantial economic losses in livestock worldwide and poses a threat to human health in endemic areas. The mainstay of control in livestock and the only drug licenced for use in humans is triclabendazole (TCBZ). TCBZ resistance has been reported on every continent and threatens effective control of fasciolosis in many parts of the world. To date, understanding the genetic mechanisms underlying TCBZ resistance has been limited to studies of candidate genes, based on assumptions of their role in drug action. Taking an alternative approach, we combined a genetic cross with whole-genome sequencing to localise a ~3.2Mbp locus within the 1.2Gbp<jats:italic>F<\/jats:italic>.<jats:italic>hepatica<\/jats:italic>genome that confers TCBZ resistance. We validated this locus independently using bulk segregant analysis of<jats:italic>F<\/jats:italic>.<jats:italic>hepatica<\/jats:italic>populations and showed that it is the target of drug selection in the field. We genotyped individual parasites and tracked segregation and reassortment of SNPs to show that TCBZ resistance exhibits Mendelian inheritance and is conferred by a dominant allele. We defined gene content within this locus to pinpoint genes involved in membrane transport, (e.g. ATP-binding cassette family B, ABCB1), transmembrane signalling and signal transduction (e.g. GTP-Ras-adenylyl cyclase and EGF-like protein), DNA\/RNA binding and transcriptional regulation (e.g. SANT\/Myb-like DNA-binding domain protein) and drug storage and sequestration (e.g. fatty acid binding protein, FABP) as prime candidates for conferring TCBZ resistance. This study constitutes the first experimental cross and genome-wide approach for any heritable trait in<jats:italic>F<\/jats:italic>.<jats:italic>hepatica<\/jats:italic>and is key to understanding the evolution of drug resistance in<jats:italic>Fasciola<\/jats:italic>spp. to inform deployment of efficacious anthelmintic treatments in the field.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011081","type":"journal-article","created":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T18:50:08Z","timestamp":1674759008000},"page":"e1011081","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["A major locus confers triclabendazole resistance in Fasciola hepatica and shows dominant inheritance"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0557-1833","authenticated-orcid":true,"given":"Nicola J.","family":"Beesley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystyna","family":"Cwiklinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Hoyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry W.","family":"Spithill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. James","family":"La Course","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana J. L.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Paterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane E.","family":"Hodgkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"ppat.1011081.ref001","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.prevetmed.2006.09.010","article-title":"Associations between anti-Fasciola hepatica antibody levels in bulk-tank milk samples and production parameters in dairy herds","volume":"78","author":"J Charlier","year":"2007","journal-title":"Prev Vet Med"},{"key":"ppat.1011081.ref002","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.vetpar.2009.09.040","article-title":"Measurement of antibodies to gastrointestinal nematodes and liver fluke in meat juice of beef cattle and associations with carcass parameters","volume":"166","author":"J Charlier","year":"2009","journal-title":"Vet Parasitol"},{"key":"ppat.1011081.ref003","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.vetpar.2011.03.009","article-title":"Association between anti-F. hepatica antibody levels in milk and production losses in dairy cows","volume":"180","author":"M Mezo","year":"2011","journal-title":"Vet Parasitol"},{"key":"ppat.1011081.ref004","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.vetpar.2012.11.030","article-title":"Investigating the impact of fasciolosis on cattle carcase performance","volume":"193","author":"MJ Sanchez-Vazquez","year":"2013","journal-title":"Vet Parasitol"},{"key":"ppat.1011081.ref005","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/ncomms1840","article-title":"Fasciola hepatica is associated with the failure to detect bovine tuberculosis in dairy cattle","volume":"3","author":"J Claridge","year":"2012","journal-title":"Nat Commun"},{"key":"ppat.1011081.ref006","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.prevetmed.2015.05.013","article-title":"Epidemiology and impact of Fasciola hepatica exposure in high-yielding dairy herds","volume":"121","author":"A Howell","year":"2015","journal-title":"Prev Vet Med"},{"key":"ppat.1011081.ref007","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S1473-3099(11)70294-8","article-title":"Global burden of human food-borne trematodiasis: a systematic review and meta-analysis","volume":"12","author":"T F\u00fcrst","year":"2012","journal-title":"Lancet Infect Dis"},{"key":"ppat.1011081.ref008","unstructured":"World Health Organisation. 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