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House mice are a major ecosystem pest, particularly threatening island ecosystems as a non-native invasive species. Rapid advances in synthetic biology offer new avenues to control pest species for biodiversity conservation. Recently, a synthetic sperm-killing gene drive construct called t-Sry has been proposed as a means to eradicate target mouse populations owing to a lack of females. A factor that has received little attention in the discussion surrounding such drive applications is polyandry. Previous research has demonstrated that sperm-killing drivers are extremely damaging to a male's sperm competitive ability. Here, we examine the importance of this effect on the t-Sry system using a theoretical model. We find that polyandry substantially hampers the spread of t-Sry such that release efforts have to be increased three- to sixfold for successful eradication. We discuss the implications of our finding for potential pest control programmes, the risk of drive spread beyond the target population, and the emergence of drive resistance. Our work highlights that a solid understanding of the forces that determine drive dynamics in a natural setting is key for successful drive application, and that exploring the natural diversity of gene drives may inform effective gene drive design. [ABSTRACT FROM AUTHOR]

The presence of selfish genetic elements can have fatal consequences for populations that harbor them. In the well known t haplotype in wild house mice, large proportions of the population die from t/t recessive lethal effects. Due to strong advantages at the gamete level (drive), t haplotypes nevertheless occur at substantial frequencies. The stable presence of a lethal is not the only effect of the t. It also distorts the fate of mutations that differentially affect male and female survival and reproduction (such as in sexual conflict), by giving male selective effects a strong advantage over female selective effects. In a recent study, we proposed polyandry as a potential counterstrategy against t deleterious effects. Here, we show that (1) the efficiency of polyandry in reducing the t frequency strongly depends on the selective context and (2) polyandry helps to reduce male-biased leverage in sex dependent selection. [ABSTRACT FROM AUTHOR]

Gene drives are genetic elements that manipulate Mendelian inheritance ratios in their favour. Understanding the forces that explain drive frequency in natural populations is a long-standing focus of evolutionary research. Recently, the possibility to create artificial drive constructs to modify pest populations has exacerbated our need to understand how drive spreads in natural populations. Here, we study the impact of polyandry on a well-known gene drive, called t haplotype, in an intensively monitored population of wild house mice. First, we show that house mice are highly polyandrous: 47% of 682 litters were sired by more than one male. Second, we find that drive-carrying males are particularly compromised in sperm competition, resulting in reduced reproductive success. As a result, drive frequency decreased during the 4.5 year observation period. Overall, we provide the first direct evidence that the spread of a gene drive is hampered by reproductive behaviour in a natural population. This study resolves a long-standing mystery of why t haplotypes, an example of selfish genes, have persisted at unexpectedly low frequencies in wild mouse populations. It shows that multiple mating by females, which is more common at higher mouse population densities, decreases the frequency of driving t haplotypes. [ABSTRACT FROM AUTHOR]