Rodent gene drives for conservation: opportunities and data needs

Abstract

Invasive rodents impact biodiversity, human health and food security worldwide. The biodiversity impacts are particularly significant on islands, which are the primary sites of vertebrate extinctions and where we are reaching the limits of current control technologies. Gene drives may represent an effective approach to this challenge, but knowledge gaps remain in a number of areas. This paper is focused on what is currently known about natural and developing synthetic gene drive systems in mice, some key areas where key knowledge gaps exist, findings in a variety of disciplines relevant to those gaps and a brief consideration of how engagement at the regulatory, stakeholder and community levels can accompany and contribute to this effort. Our primary species focus is the house mouse, Mus musculus, as a genetic model system that is also an important invasive pest. Our primary application focus is the development of gene drive systems intended to reduce reproduction and potentially eliminate invasive rodents from islands. Gene drive technologies in rodents have the potential to produce significant benefits for biodiversity conservation, human health and food security. A broad-based, multidisciplinary approach is necessary to assess this potential in a transparent, effective and responsible manner.

Keywords: biodiversity; gene drive; island; mice; rat; rodent.

Figure 1.

Gene drive designs incorporating either synthetic or naturally occurring drive mechanisms. (a) A ‘standard’ CRISPR-based gene drive that relies on homing and HDR [–46]. (b) The t-Sry approach in which spread depends on the naturally occurring t-haplotype system and a transgenic insertion of the masculinizing Sry gene [35,47]. Sperm that do not carry a t-haplotype are compromised in function and fertilization occurs with sperm carrying the t-haplotype (termed transmission ratio distortion). (c) A system that would spread through a natural drive mechanism (e.g. the t-haplotype) but incorporate CRISPR system effectors to produce genome edits and desired phenotypes. (Online version in colour.)

Figure 2.

Island and mainland population dynamics and genetics for a drive targeting a locally fixed allele on an island (figure redrawn from Sudweeks et al. [69]). This scenario models a drive with no invasion threshold, meaning there is no minimum frequency that a drive must reach in order to spread. Blue curves and axes denote population sizes, measured relative to pre-release equilibria, while red curves and axes denote allele frequencies. A small release (five homozygous drive individuals) occurs at time t = 0. Resistance is assumed to be very low on the mainland (allele frequency of just 5%)—a quite pessimistic ‘worst-case’ scenario in terms of the susceptibility of the mainland population to the drive. The drive spreads to fixation and suppresses the island population. Migration to the mainland (on average, one island individual travels to the mainland a month) means that the drive is introduced to the mainland, where it can spread through the susceptible population but not the resistant population. The total population undergoes a temporary suppression as the drive spreads through the susceptible population. The frequency of resistant alleles increases as a result of drive, and density-dependent population regulation returns the mainland population to the pre-release equilibrium level. (Online version in colour.)