Will CRISPR/Cas9 Gene Drives Spread and How Could They Be Prevented From Doing So?

Matthew Edgington, Ph.D. is at The Pirbright Institute where he is working on mathematical modelling of engineered underdominance gene drive systems in Aedes aegypti mosquitoes.

In an interesting paper published in PNAS, Tanaka, Stone and Nelson (2017) explore the potential for spatial spread of CRISPR/Cas9 gene drives. The authors examine a continuous time, spatial generalisation of the CRISPR/Cas9 population genetics model published by Unckless et al. (2015) in Genetics, restricting their attention to the limiting case with 100% conversion efficiency.

CRISPR/Cas9 gene drives are often described as “global” drive systems since they have been predicted to spread throughout a population, even when introduced at extremely low frequencies. In theory, this would enable them to rapidly spread into every member of an interbreeding population.

Exploring the full range of selective disadvantage (s) parameter space, the authors identify three behavioural regimes that they describe in terms of genetic waves.

Image result for gene drive

Insect with a gene drive with a 100% conversion efficiency.

For small selective disadvantages (s<0.5), the system produces a “pulled genetic wave”. Here the gene drive is able to spread outward from their initial release area due to diffusion of gene drive carriers and conversion of wild-types. Conversely, for large s (>0.697) the wave “reverses direction”. Here the initial release area collapses to zero as drive carriers are out-competed by wild-types.

A pattern of invasion of a non-native species of ant following its introduction in the U.S.A. that can be modeled with reaction/diffusion equations.

For intermediate values (i.e. 0.5<s<0.697), the gene drive produces a “pushed genetic wave”. Such a wave advances due to growth behind the leading edge, thus spilling over and pushing the wave front outward. This regime is of particular interest since spatial spread can only be initiated when the initial release area is above some critical size.

A strategy to prevent the spread of a CRISPR/Cas9 gene drive of the pushed wave type is then outlined. Here the authors propose that the gene drive could be engineered to spread an additional gene conferring vulnerability to a specific insecticide. This would allow for the creation of a barrier region by spraying the chosen insecticide along some chosen spatial border.

Pushed and pulled waves are two classes of traveling waves that describe reaction diffusion reactions – such as the spread of gene drives within populations. Image credit: Birzu and Korolov https://arxiv.org/pdf/1709.01601.pdf

Pushed and pulled waves are two classes of traveling waves that describe reaction diffusion reactions – such as the spread of gene drives within populations. Image credit: Birzu and Korolov https://arxiv.org/pdf/1709.01601.pdf

Numerical simulations of this strategy show that it could be effective in preventing spatial spread of a gene drive for intermediate values of s but would likely not prevent the spread of a system with small s.

A technical challenge associated with the creation of such a barrier region is that it would likely have some defects/gaps. Thus the authors simulate a scenario in which there is a gapped barrier region. In such a case a system with intermediate s can be prevented from spreading through the gap provided it is smaller than the critical release area required for such a system to spread.

This is an interesting paper that outlines some and novel results on key issues associated with CRISPR/Cas9 gene drives.

Hidenori Tanaka, Howard A. Stone, David R. Nelson (2017) Spatial gene drives and pushed genetic waves. PNAS vol. 114 no. 32 8452-8457. http://dx.doi.org/10.1073/pnas.1705868114

Additional References:
Unckless RL, Messer PW, Connallon T, Clark AG (2015) Modeling the manipulation of natural populations by the mutagenic chain reaction. Genetics 201:425–431. https://doi.org/10.1534/genetics.115.177592

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