title: Adaptive introgression of anticoagulant rodent poison resistance by hybridization between old world mice.
abstract: Polymorphisms in the vitamin K 2,3-epoxide reductase subcomponent 1 (vkorc1) of house mice (Mus musculus domesticus) can cause resistance to anticoagulant rodenticides such as warfarin [1-3]. Here we show that resistant house mice can also originate from selection on vkorc1 polymorphisms acquired from the Algerian mouse (M. spretus) through introgressive hybridization. We report on a polymorphic introgressed genomic region in European M. m. domesticus that stems from M. spretus, spans >10 Mb on chromosome 7, and includes the molecular target of anticoagulants vkorc1 [1-4]. We show that in the laboratory, the homozygous complete vkorc1 allele of M. spretus confers resistance when introgressed into M. m. domesticus. Consistent with selection on the introgressed allele after the introduction of rodenticides in the 1950s, we found signatures of selection in patterns of variation in M. m. domesticus. Furthermore, we detected adaptive protein evolution of vkorc1 in M. spretus (Ka/Ks = 1.54-1.93) resulting in radical amino acid substitutions that apparently cause anticoagulant tolerance in M. spretus as a pleiotropic effect. Thus, positive selection produced an adaptive, divergent, and pleiotropic vkorc1 allele in the donor species, M. spretus, which crossed a species barrier and produced an adaptive polymorphic trait in the recipient species, M. m. domesticus.
authors.affiliation: Department of Ecology and Evolutionary Biology, Rice University, Houston, TX 77005, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Stefan
authors.initials: S
authors.lastname: Endepols
authors.forename: Nicole
authors.initials: N
authors.lastname: Klemann
authors.forename: Dania
authors.initials: D
authors.lastname: Richter
authors.forename: Franz-Rainer
authors.initials: FR
authors.lastname: Matuschka
authors.forename: Ching-Hua
authors.initials: CH
authors.lastname: Shih
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nachman
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kohn
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D006824:Hybridization, Genetic; D051379:Mice; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D064417:Vitamin K Epoxide Reductases
chemical_list: D000925:Anticoagulants; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases