Modeling CRISPR gene drives for suppression of invasive rodents using a supervised machine learning framework.

Invasive rodent populations pose a threat to biodiversity across the globe. When confronted with these invaders, native species that evolved independently are often defenseless. CRISPR gene drive systems could provide a solution to this problem by spreading transgenes among invaders that induce population collapse, and could be deployed even where traditional control methods are impractical or prohibitively expensive. Here, we develop a high-fidelity model of an island population of invasive rodents that includes three types of suppression gene drive systems. The individual-based model is spatially explicit, allows for overlapping generations and a fluctuating population size, and includes variables for drive fitness, efficiency, resistance allele formation rate, as well as a variety of ecological parameters. The computational burden of evaluating a model with such a high number of parameters presents a substantial barrier to a comprehensive understanding of its outcome space. We therefore accompany our population model with a meta-model that utilizes supervised machine learning to approximate the outcome space of the underlying model with a high degree of accuracy. This enables us to conduct an exhaustive inquiry of the population model, including variance-based sensitivity analyses using tens of millions of evaluations. Our results suggest that sufficiently capable gene drive systems have the potential to eliminate island populations of rodents under a wide range of demographic assumptions, though only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning to identify the key parameters and processes that determine the population dynamics of a complex evolutionary system.

Ethical research engagement with Indigenous communities.

INTRODUCTION: Canada's colonial policies and practices have led to barriers for Indigenous older adults' access to healthcare and research. As a result, there is a need for Indigenous-led research and culturally safe practices. Morning Star Lodge is developing a training module to assist AgingTech researchers on ethical, culturally safe ways to engage Indigenous communities. This includes exploring Indigenous health research, community-based partnerships, reciprocal learning, and cultural safety; this is presented through a case study on ethically engaged research. METHODS: Morning Star Lodge developed a research partnership agreement with File Hills Qu'Appelle Tribal Council and established a Community Research Advisory Committee representing the eleven First Nations within the Tribal Council. The work designing the culturally safe training module is in collaboration with the Community Research Advisory Committee. RESULTS: Building research partnerships and capacities has changed the way the eleven First Nation communities within File Hills Qu'Appelle Tribal Council view research. As a result, they now disseminate the knowledge within their own networks. CONCLUSIONS: Indigenous Peoples are resilient in ensuring their sustainability and have far more community engagement and direction. Developing culturally safe approaches to care for Indigenous communities leads to self-determined research. Culturally safe training modules can be applied to marginalized demographics.

Reducing resistance allele formation in CRISPR gene drive.

CRISPR homing gene drives can convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload in a population, promising effective strategies for the control of vector-borne diseases. However, all CRISPR homing gene drives studied in insects thus far have produced significant quantities of resistance alleles that would limit their spread. In this study, we provide an experimental demonstration that multiplexing of guide RNAs can both significantly increase the drive conversion efficiency and reduce germline resistance rates of a CRISPR homing gene drive in Drosophila melanogaster We further show that an autosomal drive can achieve drive conversion in the male germline, with no subsequent formation of resistance alleles in embryos through paternal carryover of Cas9. Finally, we find that the nanos promoter significantly lowers somatic Cas9 expression compared with the vasa promoter, suggesting that nanos provides a superior choice in drive strategies where gene disruption in somatic cells could have fitness costs. Comparison of drive parameters among the different constructs developed in this study and a previous study suggests that, while drive conversion and germline resistance rates are similar between different genomic targets, embryo resistance rates can vary significantly. Taken together, our results mark an important step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further control of resistance rates.