Evolution of a Poison-Resistance Gene through Introgression

Contributed by: Zhenguo Lin

Warfarin is an anticoagulant that inhibits the synthesis of clotting factors. Because it causes internal bleeding in rats and mice, warfarin has been widely used a rodenticide since 1948. Warfarin decreases blood coagulation by inhibiting the vitamin K epoxide reductase (VKOR), an enzyme involved in the carboxylation of several blood coagulation proteins.

             After merely 10 years of introduction of warfarin as a rodenticide, warfarin resistant mouse or rats have been found. The resistance to warfarin of house mice (Mus musculus domesticus) was found to be due to some nonsynonymous single-nucleotide polymorphisms (SNPs) in the vitamin K epoxide reductase subcomponent 1 (vkorc1) that encodes the warfarin-sensitive component of VKOR.

Song et al. (2011) recently found that the polymorphisms of vkorc1 in resistant house mice were acquired from the Algerian mouse (Mus spretus), a species known to be naturally resistant to warfarin, through introgressive hybridization (1).

The Algerian mouse and house mouse diverged 1.5–3 million years ago and the distributions of the two species has some overlaps in Spain and northern Africa. The hybridization between the two species is not common and only some female offspring are fertile. However, it is surprising that the piece of DNA that contain warfarin resistant gene can spread quickly in the house mouse populations in a few decades. For example, the vkorc1 gene in 27 of 29 house mice examined in Spain was entirely or partly originated from Algerian mice. Similar cases were also observed in 16 of 50 house mice in Germany, where Algerian mice do not exist (1). Although it is believed that interspecific hybrids have severe disadvantages, this study suggests that hybridization can be an important way for the evolution of a specific character.

Distribution of vkorc1 genotypes in Western European M. m. domesticus. The hatched area depicts the native range of M. spretus. The house mouse (Mus musculus spp.) has become a cosmopolitan species and now is occurring across the entire area depicted and beyond. Pie charts show the frequencies of pure vkorc1 of M. m. domesticus origin (vkorc1^dom) (pink, genotypes 1–6 in A), genotypes that correspond to the complete M. spretus vkorc1 allele or share parts of it in the form of heterozygosity and/or intragenic recombination (all vkorc1^spr, yellow, genotypes 8–20 in A), and ambiguous genotypes (genotype 7, green). Countries sampled in this study are shaded in gray. Sampling locations (some overlapping as a result of proximity) are shown as triangles (pink, vkorc1^spr absent; yellow, vkorc1^spr present). From Song et al. (2011).

References

1. Song, Y.,  Endepols, S.,  Klemann, N., Richter, D.,  Matuschka, F.R., Shih, C.H., Nachman, M.W., and Kohn, M.H. 2011. Adaptive introgression of anticoagulant rodent poison resistance by hybridization between Old World mice. Current Biology 21:1296-1301