Synthetic sequence entanglement augments stability and containment of genetic information in cells

Science
Tomasz BlazejewskiHarris H Wang

Abstract

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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Citations

Apr 25, 2020·Protein Engineering, Design & Selection : PEDS·Ichiro Matsumura, Donian Chyong
Sep 13, 2019·Nucleic Acids Research·Jonathan CallesDrew Endy
Nov 3, 2020·Journal of Industrial Microbiology & Biotechnology·Peter Rugbjerg, Lisbeth Olsson
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Jan 13, 2021·Nature Chemical Biology·Sung Sun YimHarris H Wang
Dec 4, 2020·Nature Communications·Alessandro L V CoradiniIan M Ehrenreich
Feb 27, 2021·Frontiers in Microbiology·Ilenne Del ValleLauren B Stadler
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Oct 7, 2021·Nature Reviews. Genetics·Bradley W WrightPaul R Jaschke
Oct 9, 2021·PLoS Computational Biology·Antoine L DecrulleAriel B Lindner

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