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Biology subjects

Oakes, N.

Publications and source records attributed to Oakes, N..

2 recordsLinked to original sources

Modeling CRISPR gene drives for suppression of invasive rodents

Invasive rodent populations pose a threat to biodiversity across the globe. When confronted with these new 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. Such systems might 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 and allows for overlapping generations and a fluctuating population size. Our model 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, but only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning for identifying the key parameters and processes that determine the population dynamics of a complex evolutionary system.

ecology↗

Reducing resistance allele formation in CRISPR gene drives

CRISPR gene drives can efficiently convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. This mechanism could be used, for example, to rapidly disseminate a genetic payload through a population, promising novel strategies for the control of vector-borne diseases. However, all CRISPR gene drives tested have produced significant quantities of resistance alleles that cannot be converted to drive alleles and would likely prevent these drives from spreading in a natural population. In this study, we assessed three strategies for reducing resistance allele formation. First, we directly compared drives with the nanos and vasa promoters, which showed that the vasa drive produced high levels of resistance alleles in somatic cells. This was not observed in the nanos drive. Another strategy was the addition of a second gRNA to the drive, which both significantly increased the drive conversion efficiency and reduced the formation rate of resistance alleles. Finally, to minimize maternal carryover of Cas9, we assessed the performance of an autosomal drive acting in the male germline, and found no subsequent formation of resistance alleles in embryos. Our results mark a step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further reduction of resistance rates.

genetics↗