Journal
NUCLEIC ACIDS RESEARCH
Volume 41, Issue 4, Pages 2769-2778Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks1356
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Funding
- National Institutes of Health (NIH) [R00 NS060996, R01 NS070911, R01DA031367, F31NS077842, F31NS077844]
- Edward Mallinckrodt Jr. Foundation
- Rita Allen Foundation
- Brain and Behavior Research Foundation
- Della Martin Fund
- Millard and Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology
- NIH
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Zinc-finger nucleases (ZFNs) and TAL effector nucleases (TALENs) have been shown to induce targeted mutations, but they have not been extensively tested in any animal model. Here, we describe a large-scale comparison of ZFN and TALEN mutagenicity in zebrafish. Using deep sequencing, we found that TALENs are significantly more likely to be mutagenic and induce an average of 10-fold more mutations than ZFNs. We observed a strong correlation between somatic and germ-line mutagenicity, and identified germ line mutations using ZFNs whose somatic mutations rates are well below the commonly used threshold of 1%. Guidelines that have previously been proposed to predict optimal ZFN and TALEN target sites did not predict mutagenicity in vivo. However, we observed a significant negative correlation between TALEN mutagenicity and the number of CpG repeats in TALEN target sites, suggesting that target site methylation may explain the poor mutagenicity of some TALENs in vivo. The higher mutation rates and ability to target essentially any sequence make TALENs the superior technology for targeted mutagenesis in zebrafish, and likely other animal models.
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