Gene drive designs for efficient and localisable population suppression using Y-linked editors.

The sterile insect technique (SIT) has been successful in controlling some pest species but is not practicable for many others due to the large number of individuals that need to be reared and released. Previous computer modelling has demonstrated that the release of males carrying a Y-linked editor that kills or sterilises female descendants could be orders of magnitude more efficient than SIT while still remaining spatially restricted, particularly if combined with an autosomal sex distorter. In principle, further gains in efficiency could be achieved by using a self-propagating double drive design, in which each of the two components (the Y-linked editor and the sex ratio distorter) boosted the transmission of the other. To better understand the expected dynamics and impact of releasing constructs of this new design we have analysed a deterministic population genetic and population dynamic model. Our modelling demonstrates that this design can suppress a population from very low release rates, with no invasion threshold. Importantly, the design can work even if homing rates are low and sex chromosomes are silenced at meiosis, potentially expanding the range of species amenable to such control. Moreover, the predicted dynamics and impacts can be exquisitely sensitive to relatively small (e.g., 25%) changes in allele frequencies in the target population, which could be exploited for sequence-based population targeting. Analysis of published Anopheles gambiae genome sequences indicates that even for weakly differentiated populations with an FST of 0.02 there may be thousands of suitably differentiated genomic sites that could be used to restrict the spread and impact of a release. Our proposed design, which extends an already promising development pathway based on Y-linked editors, is therefore a potentially useful addition to the menu of options for genetic biocontrol.

Systematic evaluation of high-throughput PBK modelling strategies for the prediction of intravenous and oral pharmacokinetics in humans.

Physiologically based kinetic (PBK) modelling offers a mechanistic basis for predicting the pharmaco-/toxicokinetics of compounds and thereby provides critical information for integrating toxicity and exposure data to replace animal testing with in vitro or in silico methods. However, traditional PBK modelling depends on animal and human data, which limits its usefulness for non-animal methods. To address this limitation, high-throughput PBK modelling aims to rely exclusively on in vitro and in silico data for model generation. Here, we evaluate a variety of in silico tools and different strategies to parameterise PBK models with input values from various sources in a high-throughput manner. We gather 2000 + publicly available human in vivo concentration-time profiles of 200 + compounds (IV and oral administration), as well as in silico, in vitro and in vivo determined compound-specific parameters required for the PBK modelling of these compounds. Then, we systematically evaluate all possible PBK model parametrisation strategies in PK-Sim and quantify their prediction accuracy against the collected in vivo concentration-time profiles. Our results show that even simple, generic high-throughput PBK modelling can provide accurate predictions of the pharmacokinetics of most compounds (87% of Cmax and 84% of AUC within tenfold). Nevertheless, we also observe major differences in prediction accuracies between the different parameterisation strategies, as well as between different compounds. Finally, we outline a strategy for high-throughput PBK modelling that relies exclusively on freely available tools. Our findings contribute to a more robust understanding of the reliability of high-throughput PBK modelling, which is essential to establish the confidence necessary for its utilisation in Next-Generation Risk Assessment.