Are Non-Target Mutations via CRISPR in Plants a Concern? – Out-of-the-Box

Paul Vincelli

I provide outreach on GE crops for the University of Kentucky, so I am very attentive to questions of risks and benefits regarding CRISPR-based genetic modification. I occasionally have heard or read expressions of concern regarding the capacity of CRISPR/Cas9 to induce genetic change in DNA sequences that are highly similar—but not identical—to sequences that are the target of the designed single-guide RNA. These are often referred to as “non-target mutations.

While I initially considered this to be a potentially important issue, over time and through study and reflection, I have come to seriously question the notion that this represents a significant concern. Here are my reasons:

• 1. In plants, reported off-target rates are commonly low to non-existent [1-13];
• 2. Strategies for reducing off-target mutations continue to be researched and published [9, 13-20];
• 3. Off-target mutations can be monitored via whole-genome sequencing;
• 4. In sexually reproducing crops, undesirable mutations can be segregated out [15];
• 5. In contrast to clinical applications in humans, the relevance of non-target genetic changes during crop improvement is questionable.

 Clearly, eliminating non-target genetic changes during human gene therapy would be highly desirable. The same may be said for gene drive-modified organisms [21]. However, in the case of crop plants, I am aware of no evidence suggesting that non-target genetic changes in a crop improvement program present an intrinsic risk to biosafety or to human health. Indeed, more genetic, transcriptomic, and proteomic change is commonly observed from conventional breeding that from GE [22-35]; therefore, one could postulate greater off-target risks from conventional breeding than from CRISPR-based technologies. (My intention is not to raise anxieties over the safety of either general approach to crop improvement. Genetic crop improvement has one of the safest records of all human endeavors. My intention is merely to put genetic changes associated with CRISPR in perspective.)

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