ACCEPTED MANUSCRIPT Concerning RNA-guided gene drives for the alteration of wild populations

Introduction Natural Gene Drives Endonuclease Gene Drives Engineered Gene Drives RNA-guided Genome Editing Via the Cas9 Nuclease Will RNA-Guided Gene Drives Enable Us to Edit the Genomes of Wild Populations? Cutting Specificity Copying Evolutionary Stability Development Time Gene Drive Limitations Safeguards and Control Strategies Reversibility Immunization Precisely Targeting Subpopulations Limiting Population Suppression Applications of RNA-Guided Gene Drives Eradicating Vector-Borne Disease Agricultural Safety and Sustainability Controlling Invasive Species Development and Release Precautions Transparency, Public Discussion, and Evaluation Discussion References Box 1. Could gene drives alter human populations? Box 2. Could gene drives affect domesticated animals or crops? Box 3. What types of genes can be edited using gene drives? F ig . 1. Endonuclease gene drive replication. Fig. 2. Consequences and timing of gene drive replication. Fig. 3. RNA-guided genome editing via Cas9. Fig. 4. Technical advantages of RNA-guided gene drives. Fig. 5. Methods of reversing, preventing, and controlling the effects and spread of gene drives. Fig. 6. Controlling populatio n suppression. Fig. 7. Potential applications of RNA-guided gene drives. Fig. 8. Containment strategies and ecological risk. eLife (2014) doi:10.7554/eLife.03401 1 Table of