Distribution and frequency of VKORC1 sequence variants conferring resistance to anticoagulants inMus musculus

Abstract

House mouse tissue samples from 30 populations in Germany, Switzerland and the Azores were analyzed for sequence changes in the gene VKORC1, which potentially confer resistance to anticoagulant rodenticides. Except for one population originating from south Germany, sequence variants were found in individuals from all locations analyzed (29 out of 30 sites surveyed), with less than 10 % of the individuals matching the wild-type genotype. The most frequent and widespread amino acid substitutions were Leu128Ser, Tyr139Cys and a group of linked sequence changes (Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu). These three genotypes occurred either alone or in combination with each other or with other less frequent sequence changes. Where they occurred as the sole variant, the proportion of homozygous animals was 72-83 %, suggesting a high selection pressure due to permanent pest control in these populations.An evaluation of published data revealed that the three frequent sequence changes found are associated with a substantial loss of rodenticide efficacy of first generation anticoagulants (e.g. warfarin, coumatetralyl) as well as the second generation compound bromadiolone and most probably also difenacoum. Further studies are required to investigate the effect on compounds of higher potency, in particular, where combinations of sequence changes occur in one individual.

Adaptative evolution of theVkorc1gene inMus musculus domesticusis influenced by the selective pressure of anticoagulant rodenticides

“…These studies allowed to detect in humans 27 mutations in the coding sequence of the Vkorc1 gene (Bodin, Horellou, Flaujac, Loriot, & Samama, 2005; Bodin, Perdu, Diry, Horellou, & Loriot, 2008; D'Andrea et al., 2005; Harrington, Siddiq, Allford, Shearer, & Mumford, 2011; Harrington et al., 2008; Loebstein et al., 2007; Osman, Enström, Arbring, Söderkvist, & Lindahl, 2006; Peoc'h, Pruvot, Gourmel, Dit Sollier, & Drouet, 2009; Rieder et al., 2005; Rishavy, Usubalieva, Hallgren, & Berkner, 2011; Rost et al., 2004; Schmeits et al., 2010; Watzka et al., 2011; Wilms, Touw, Conemans, Veldkamp, & Hermans, 2008). In rats, 15 missense mutations in the Vkorc1 gene of Rattus norvegicus have been described in Europe (Grandemange, Lasseur, Longin‐Sauvageon, Benoit, & Berny, 2010; Haniza et al., 2015; Pelz et al., 2005, 2012; Rost et al., 2004). The number of mutations reported in this gene is thus comparable between rats, mice, and humans.…”

“…In mice, 15 mutations have been detected in Europe in this study and in a previous study performed in 2012 (Pelz et al., 2012). Frequency of mice carriers for Vkorc1 mutations was found to be extremely elevated in both studies.…”

Dicoumarol: A Drug which Hits at Least Two Very Different Targets in Vitamin K Metabolism

“…Based on the structure of the cyanobacterial enzyme, it was suggested that warfarin binds at the same site at the quinone seen in the structure (and that vitamin K epoxide would also interact at this site) [47]. This is consistent with the locations of some of the mutations which alter the sequence of rat VKOR conferring resistance to warfarin and those which are associated with hereditary clotting deficiencies in humans [55,[62][63][64][65][66][67]. Many of these variant forms of VKOR have lower catalytic activity than the wild-type and it is presumed that this loss of fitness is a "price worth paying" for resistance to rat poison [68].…”

Indigenous house mice dominate small mammal communities in northern Afghan military bases

“…As airlifts to Afghanistan were conducted from both areas (Cologne airport and Leipzig airport), animals from Western Germany and North Western Czech Republic (representing the Central European M. m. musculus population) were selected. The trapping of control animals for astrovirus and herpesvirus investigations at five sites in Germany and one site in the United Kingdom have been reported previously [13,17,18]. As no morphological vouchers could be preserved in this study, some preliminary species identifications were based on the photographic documentation and comparisons with museum specimens.…”

“…Because of these high birth rates, house mouse populations are characterized by a strong resilience towards predation and pest control measures. These animals are considered an invasive species especially on island locations and caused devastations to the biodiversity of New Zealand as well as several island ecosystems of the South Atlantic and Indian Oceans during European exploration in the 19 th century [13,14]. This may be due to quick genotypic and phenotypic adaptations (e.g.…”