Telling Tales to Recode Zebrafish Genome: Chemical Reprogramming of Zebrafish for High-Efficiency Genome Editing

As next-generation sequencing costs continue to fall, whole-genome and exome-genome sequencing and genome-wide association studies are generating more candidate human disease genes than ever. However, the function and role of these genes in the human disease remain to be discovered. Model organisms are crucial for efficient and robust investigation of candidate human disease genes in vivo. Due to its short reproductive cycle, ease of maintenance and physiological similarity to humans, zebrafish provides a powerful model system for not only investigating these genes but also for rapid large-scale drug screening. However, inability to alter the genome with ease and accuracy has been a major challenge. Genome editing tools such as CRISPR-Cas9 and TALENs have recently become available allowing introduction of heritable and precise sequence modifications in the genome. Both of these tools induce highly precise, locus-specific double strand breaks in the genome to generate multiple target-specific gene knock-ins and knock-outs in vivo. These exciting genome editing tools redefine the boundaries of the medical research by allowing scientists to generate various human disease models in model organisms much more quickly than before. We can now, investigate the functional role of individual genes much faster and readily alter multiple genes in cells at once to reveal their interactions. In this study we report a novel way to reprogram zebrafish embryos for high efficiency homology-directed genome editing. Our work further presents the application of these powerful tools to generate human disease models in zebrafish.