The population dynamics of genetically determined resistance to warfarin in Rattus norvegicus from mid Wales

Abstract

SUMMARYDominant warfarin resistance and a recessive haemorrhagic trait are apparently controlled by the same allele Rw5.Twenty-eight F5 litters and 18 backcross litters of wild rats were scored for resistance when 8 weeks of age. There was a deficiency of resistant males in the F2 litters whereas phenotypic ratios were close to expectation in F5 females and hackcrosses. Any deficiency of resistant males in F5 litters could be due to the selective death of the Rw5Rw5 genotype. The size of F5 and backcross litters at birth is similar whereas by 8 weeks the former are significantly smaller than the latter.Samples of rats from populations in mid Wales were scored for resistance. There was a significant decline in the frequency of phenotypic resistance in one large population (X 500) starting when the frequency of the Rw5 allele was relatively low (c. 0l0-023). Since few alleles can be lost by selective death of Rw5Rw5 males in these circumstances it appears that, in the absence of warfarin, the heterozygote may also be at a selective disadvantage.Where rats are intensively poisoned with warfarin both Rw2 and its alternative Rw' are maintained in populations by heterozygous advantage. The ecological unreality of the concept of segregational load is discussed.Strong selection influences the frequency of the alleles of Rio. Chance must also have an important role. Populations of rats in rural areas are widely scattered and sometimes small in size. There is an unpredictable amount of movement between these populations which occur in very heterogeneous environments.

Relationships between genetic polymorphism and herbicide resistance within Alopecurus myosuroides Huds.

“…This has occurred in fungi (Leroux, 1987), insects (Georghiou, 1990), mammals (Bishop et al, 1977) and flowering plant weeds (Darmency & Gasquez, 1990). More than 80 resistant weed species have already been described (Lebaron, 1991).…”

Natural selection mapping of the warfarin-resistance gene

“…This system is a well documented example of an evolutionary response to natural selection (22)(23)(24) and has several other characteristics that make it well suited for testing the approach. Resistance has a simple genetic basis (25,26), with a physiological effect that can be measured with a blood clotting response (BCR) test (27,28).…”

Vitamin K deficiency syndromes in warfarin-resistant brown rats (Rattus norvegicus)

“…Maternal care did not improve in laboratory-reared animals. It was sometimes possible to foster abandoned pups onto a lactating Wistar rat having young of about the same age (Bishop et al, 1977). Table 1 shows the mortality observed in F 2 and backcross matings in wild-reared litters between weaning (4 weeks) and resistance testing age (8 weeks).…”

“…Resistance was determined by measuring the percentage clotting activity (PCA) of each animal's blood before and after an injection of a mixed solution of vitamin K oxide and warfarin (Greaves, Redfern, Ayres & Gill, 1977;Bishop et al, 1977). Occasionally rats had very low initial PCA values «20%) indicating a deficiency of the vitamin K dependent blood clotting factors.…”

“…When compared to warfarinsusceptible animals (Rw'Rw'), homozygous resistant (Rw 2 Rw 2 ) and heterozygous resistant (Rw'Rw 2 ) rats were found to have respectively a 20-fold and 2-fold increase in vitamin K requirement (Hermodson, Suttie & Link, 1969). Bishop, Hartley & Partridge (1977) found in the laboratory that litter sizes of F 2 (Rw'Rw 2 x Rw'Rw 2 ) matings were significantly smaller than backcross matings (Rw 1 Rw 2 x Rw1Rw l , or reciprocal) at 8 weeks of age. This suggested that selective death was taking place during the first few weeks of life in F 2 litters.…”