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120 The future of genome editing in food animal species


 Genome editing refers to the use of targeted nucleases to introduce double-stranded breaks in DNA at a specific sequence in the genome. The cell can then repair this break using either the error-prone, non-homologous end joining (NHEJ) pathway which often results in a small insertion or deletion. This can inactivate or “knock-out” a gene if the repair introduces a missense or nonsense frameshift mutation in the coding region of the protein encoded by that gene. Alternatively, the break can be repaired via the homology-directed repair (HDR) pathway which relies on a nucleic acid template to guide the repair. Depending upon the template, the directed repair can be as simple as a single nucleotide change, or as complicated as an entire transgene integration. Editing offers an opportunity for geneticists to precisely introduce useful genetic alterations into animal breeding programs. Some examples include a knock-out of the CD163 cellular receptor of porcine reproductive and respiratory syndrome virus (PRRSV) which renders pigs resistant to infection by that virus, and the replacement of the horned allele in dairy cattle with the Celtic (PC) POLLED allele resulting in genetic hornlessness. For editing to be useful, it will need to seamlessly integrate with genetic improvement program design. This will ultimately require introducing edits into multiple elite lines to avoid genetic bottlenecks. This requirement is at odds with the process-based trigger and event-based regulatory approach that has been proposed for gene edited food animals by the US Food and Drug Administration (FDA). The 2017 draft FDA regulatory guidance 187 states that “intentional” genomic alterations introduced by genome editing will be regulated as new animal drugs, irrespective of product novelty or risk, necessitating lengthy multigenerational safety evaluations. The high costs associated with new animal drug approval will dramatically curtail the use of genome editing in food animal species.