Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance

Abstract

SUMMARYResistance to warfarin and an increased vitamin K requirement appear to be pleiotropic effects of the same allele (Rw 2). In a natural population containing resistant individuals where the use of warfarin is discouraged the change in the frequency of resistance should reflect the relative fitnesses of the three possible genotypes.A large polymorphic population of rats was extensively poisoned with warfarin and the level of resistance monitored regularly for a period of 18 months after withdrawal of the poison. During this period the proportion of resistant animals in live-capture samples decreased significantly from approxi-. mately 80 per cent to 33 per cent. This decline is consistent with a hypothesis of reduced fitness of both RwZRw2 and Rw'Rw2 genotypes relative to Rw'Rw' under natural conditions. The relative fitnesses of these genotypes were calculated using an optimisation method based on least squares analysis. These estimates were: Rw2Rw2 (0.46), Rw'Rw2 (077) and Rw1Rw' (100).Homozygous resistant individuals were found in some of the samples, confirmlog that the Rw2 allele does not act as a recessive lethal, although it must be extremely disadvantageous.Some heterogeneity was observed in the proportion of resistant animals in samples taken from different areas of the farm building complex. This could reflect stochastic processes influencing the Rw2 allele frequency in small peripheral populations.

Multiple allelism at the locus controlling warfarin resistance in the Norway rat

“…Consequently, and in contrast to many soluble enzymes, they tend to be conserved by natural selection in a monomorphic state. This picture is consistent with the general observation that warfarin-resistance alleles seem to be very rare until selection with warfarin-type poisons has been practised for several years and that, in populations that have become polymorphic for resistance, there are large differences in relative fitness between different genotypes (Greaves, Redfern, Ayres & Gill, 1977;Partridge, 1979). It is thus of some interest not only that different resistant mutations have occurred in the Scottish and Welsh rat populations but also that the same membrane-bound reductase may have been modified in different ways to produce two different forms of resistance.…”

Natural selection mapping of the warfarin-resistance gene

“…First, a metaanalysis of 1,276 published selection coefficients documented that intense selection may be common in natural populations, and selection coefficients can attain values similar in magnitude to those of artificial breeding experiments (1). Roughly 18% of selection coefficients measured in unperturbed natural populations were higher than 0.6, which is similar in magnitude to selection coefficients associated with warfarin selection (22)(23)(24). Second, the natural environment generally is spatially and temporally heterogeneous, and, therefore, the relative fitness of genotypes is constantly changing (2).…”

“…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).…”

“…Anticoagulant selection is intense, with on average 95% mortality (range Ϸ60-100%) (32). Population resistance levels can change rapidly with anticoagulant application (22)(23)(24)33), and the frequency and intensity of anticoagulant selection varies among populations (22)(23)(24)33).…”

Relationship between resistance factors and treatment efficacy when bromadiolone was used against anticoagulant-resistant Norway rats (Rattus norvegicusBerk.) in Wales

“…to anticoagulant rodenticides has received considerable study since it was discovered in the early 1960s (Drummond 1966). The speed of spread of resistance was investigated (Greaves and Rennison 1973) and the pleiotropic effects of the possession of the Welsh anticoagulant resistance gene, involving an increased requirement for dietary vitamin K, was also studied (Partridge 1979). Subsequently, Welsh farms infested with resistant rats were used to check the field efficacy of the majority of the anticoagulant rodenticides now in common use (Rennison and Hadler 1975;Rennison and Dubock 1978;Richards 1981;Buckle 1986).…”