Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 4, Pages 2564-2576Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1212
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Funding
- National Science Foundation (NSF)
- US National Institutes of Health (NIH)
- Foundation for the NIH through the Gates Foundation Grand Challenges in Global Health Initiative [GM084433, RL1CA133832]
- Howard Hughes Medical Institute (HHMI)
- NIH
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Homing endonucleases (HEs) can be used to induce targeted genome modification to reduce the fitness of pathogen vectors such as the malaria-transmitting Anopheles gambiae and to correct deleterious mutations in genetic diseases. We describe the creation of an extensive set of HE variants with novel DNA cleavage specificities using an integrated experimental and computational approach. Using computational modeling and an improved selection strategy, which optimizes specificity in addition to activity, we engineered an endonuclease to cleave in a gene associated with Anopheles sterility and another to cleave near a mutation that causes pyruvate kinase deficiency. In the course of this work we observed unanticipated context-dependence between bases which will need to be mechanistically understood for reprogramming of specificity to succeed more generally.
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