Modelling the suppression of a malaria vector using a CRISPR-Cas9 gene drive to reduce female fertility

Abstract

Background: Gene drives based on CRISPR-Cas9 technology are increasingly being considered as tools for reducing the capacity of mosquito populations to transmit malaria, and one of the most promising options is driving endonuclease genes that reduce the fertility of female mosquitoes. In particular, there is much interest in constructs that target the conserved mosquito doublesex (dsx) gene such that the emergence of functional driveresistant alleles is unlikely. Proof of principle that these constructs can lead to substantial population suppression has been obtained in population cages, and they are being evaluated for use in sub-Saharan Africa. Here, we use simulation modelling to understand the factors affecting the spread of this type of gene drive over a one millionsquare kilometre area of West Africa containing substantial environmental and social heterogeneity. Results: We found that a driving endonuclease gene targeting female fertility could lead to substantial reductions in malaria vector populations on a regional scale. The exact level of suppression is influenced by additional fitness costs of the transgene such as the somatic expression of Cas9, and its deposition in sperm or eggs leading to damage to the zygote. In the absence of these costs, or of emergent drive-resistant alleles that restore female fertility, population suppression across the study area is predicted to stabilise at~95% 4 years after releases commence. Small additional fitness costs do not greatly affect levels of suppression, though if the fertility of females whose offspring transmit the construct drops by more than~40%, then population suppression is much less efficient. We show the suppression potential of a drive allele with high fitness costs can be enhanced by engineering it also to express male bias in the progeny of transgenic males. Irrespective of the strength of the drive allele, the spatial model predicts somewhat less suppression than equivalent non-spatial models, in particular in highly seasonal regions where dry season stochasticity reduces drive efficiency. We explored the robustness of these results to uncertainties in mosquito ecology, in particular their method of surviving the dry season and their dispersal rates. Conclusions: The modelling presented here indicates that considerable suppression of vector populations can be achieved within a few years of using a female sterility gene drive, though the impact is likely to be heterogeneous in space and time.

Suppression gene drive in continuous space can result in unstable persistence of both drive and wild‐type alleles

“…Outcomes consistent with chasing behaviour have already been observed in other models of suppression gene drives in structured populations (Bull et al, 2019; North et al, 2019, 2020). In these studies, it was suggested that the drive efficiency should be high enough to avoid stochastic drive loss but should not be so high that the drive eliminates patches of wild‐type alleles and itself before being able to spread to an adjacent region.…”

“…In this study, we systematically explore how a population model that explicitly incorporates continuous space affects the dynamics and outcome of a suppression gene drive release. We show that a dynamic phenomenon we term “chasing,” which is similar to the pattern of local eradication followed by recolonization observed in previous studies (Bull et al, 2019; North et al, 2019, 2020), can lead to long‐term, unstable coexistence between drive and wild‐type alleles. We analyse the propensity of different types of suppression drives to produce such chasing dynamics and show how this phenomenon depends on the ecological and demographic parameters of the population.…”

“…Environmental variation, such as those that affect migration and low‐density growth rates, may also facilitate chasing if regions exist with ecological parameters that are more amenable to chasing, which could then serve as “seeds” for recurrent, temporary expansions of wild‐type individuals into surrounding areas that are less amenable to chasing. In a study of gene drive suppression in a network of linked panmictic demes, chasing‐like behaviour was more frequent in areas with strong seasonality, and long‐range dispersal did not have a large effect on suppression outcomes (North et al, 2019, 2020).…”

“…Panmictic population models have been useful in identifying the parameters that would allow a gene drive to spread most effectively through a population, as well as studying phenomena such as the evolution of resistance (Burt, 2003; Deredec et al, 2008, 2011; Prowse et al, 2017). Yet it has also become clear that to accurately understand the full range of outcomes of a gene drive release, spatial factors must be explicitly considered (Beaghton et al, 2016; Eckhoff et al, 2017; Huang et al, 2011; Legros et al, 2013; North et al, 2013, 2019, 2020). Panmictic models typically predict, for instance, that a suppression drive will either successfully eliminate a population, be quickly lost, reach a stable equilibrium with wild‐type alleles or fail due to formation of resistance alleles (Beaghton et al, 2017; Burt, 2003; Champer, Oh, et al, 2020; Deredec et al, 2008, 2011; Prowse et al, 2017).…”

Modeling CRISPR gene drives for suppression of invasive rodents

“…In contrast with the other two drives, the Y-shredder is not a homing drive (though homing sex-chromosome shredder drives have been proposed and constructed 47,66–68 ). The drive is located on the X-chromosome and shreds the Y-chromosome in germline cells.…”