Evaluating strategies for reversing CRISPR-Cas9 gene drives

Abstract

A gene drive biases inheritance of a gene so that it increases in frequency within a population even when the gene confers no fitness benefit. There has been renewed interest in environmental releases of engineered gene drives due to recent proof of principle experiments with the CRISPR-Cas9 system as a drive mechanism. Release of modified organisms, however, is controversial, especially when the drive mechanism could theoretically alter all individuals of a species. Thus, it is desirable to have countermeasures to reverse a drive if a problem arises. Several genetic mechanisms for limiting or eliminating gene drives have been proposed and/or developed, including synthetic resistance, reversal drives, and immunizing reversal drives. While predictions about efficacy of these mechanisms have been optimistic, we lack detailed analyses of their expected dynamics. We develop a discrete time model for population genetics of a drive and proposed genetic countermeasures. Efficacy of drive reversal varies between countermeasures. For some parameter values, the model predicts unexpected behavior including polymorphic equilibria and oscillatory dynamics. The timing and number of released individuals containing a genetic countermeasure can substantially impact outcomes. The choice among countermeasures by researchers and regulators will depend on specific goals and population parameters of target populations.

Modulating CRISPR gene drive activity through nucleocytoplasmic localization of Cas9 in S. cerevisiae

“…The ability to modify an entire population with a genetic element of choice presents numerous advantages including optimizing agricultural crops and animals, prevention of human disease, and ecological control on a large scale. However, ongoing testing of optimal designs including safeguards and controllable drives warrant further research and recent progress has been made in current systems 25,26,[54][55][56] . Previous efforts (both computational and experimental) have highlighted a variety of components that might serve as a platform for control or inhibition of gene drives 21,26,29,30 .…”

“…There are numerous applications of gene drive biotechnology to control and alter biological populations including global challenges such as eliminating insect-borne diseases [16][17][18] . Recent experimental [19][20][21][22][23][24] and computational studies [25][26][27] highlight the potential of GD systems. However, there remain many unknowns surrounding implementation and management of this new technology (including accidental or malicious release of such a system sans any safeguard or inhibitory mechanism).…”

Gene drive to reduce malaria transmission in sub-Saharan Africa

“…For CRISPR-based systems, the latter could be as simple as a gRNA that targets the Cas9 nuclease (Wu, Luo, and Gao 2016). These and other potential strategies deserve careful modelling (Vella et al 2017).…”

The promise and peril of CRISPR gene drives

“…We note that overwriting and reversal drives described here are subject to the same caveats in terms of genetic variation, inbreeding, and/or mating competitiveness discussed above for initial drives. Modeling of various drive control strategies has also suggested unexpected behaviors in certain situations and so more work is necessary to understand if such safeguards will be effective.…”