Journal
SCIENCE
Volume 365, Issue 6453, Pages 595-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav5477
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Funding
- DARPA [W911NF-15-2-0065]
- Sloan Foundation [FR-2015-65795]
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In synthetic biology, methods for stabilizing genetically engineered functions and confining recombinant DNA to intended hosts are necessary to cope with natural mutation accumulation and pervasive lateral gene flow. We present a generalizable strategy to preserve and constrain genetic information through the computational design of overlapping genes. Overlapping a sequence with an essential gene altered its fitness landscape and produced a constrained evolutionary path, even for synonymous mutations. Embedding a toxin gene in a gene of interest restricted its horizontal propagation. We further demonstrated a multiplex and scalable approach to build and test > 7500 overlapping sequence designs, yielding functional yet highly divergent variants from natural homologs. This work enables deeper exploration of natural and engineered overlapping genes and facilitates enhanced genetic stability and biocontainment in emerging applications.
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