دورية أكاديمية
Engineering gene overlaps to sustain genetic constructs in vivo.
| العنوان: | Engineering gene overlaps to sustain genetic constructs in vivo. |
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| المؤلفون: | Decrulle, Antoine L., Frénoy, Antoine, Meiller-Legrand, Thomas A., Bernheim, Aude, Lotton, Chantal, Gutierrez, Arnaud, Lindner, Ariel B. |
| المصدر: | PLoS Computational Biology; 10/8/2021, p1-19, 19p, 1 Diagram, 3 Graphs |
| مصطلحات موضوعية: | BIOENGINEERING, GENE regulatory networks, MICROBIAL genomes, NATURAL selection, BIOLOGICAL systems, SYNTHETIC biology |
| مستخلص: | Evolution is often an obstacle to the engineering of stable biological systems due to the selection of mutations inactivating costly gene circuits. Gene overlaps induce important constraints on sequences and their evolution. We show that these constraints can be harnessed to increase the stability of costly genes by purging loss-of-function mutations. We combine computational and synthetic biology approaches to rationally design an overlapping reading frame expressing an essential gene within an existing gene to protect. Our algorithm succeeded in creating overlapping reading frames in 80% of E. coli genes. Experimentally, scoring mutations in both genes of such overlapping construct, we found that a significant fraction of mutations impacting the gene to protect have a deleterious effect on the essential gene. Such an overlap thus protects a costly gene from removal by natural selection by associating the benefit of this removal with a larger or even lethal cost. In our synthetic constructs, the overlap converts many of the possible mutants into evolutionary dead-ends, reducing the evolutionary potential of the system and thus increasing its stability over time. Author summary: Genomes are translated by triplets of nucleotides on two different strands, allowing for six different reading frames. This permits the existence of gene overlaps, often observed in microbial genomes, where two different proteins are encoded on the same piece of DNA, but in different reading frames. Gene overlaps are classically considered an obstacle for both evolution and genetic engineering, as mutations in overlapping regions likely have pleitrotropic effects on several genes. In 2013, we identified specific evolutionary scenarios where the decrease in evolutionary potential caused by gene overlaps could instead be advantageous and selected for. In this work, we demonstrate the use of gene overlaps in another context where reducing evolutionary potential can be useful: preventing evolution from inactivating synthetic circuits. We show that gene overlaps can be engineered to increase the evolutionary stability of genes that are costly to their hosts, by entangling these costly genes with essential genes. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: | Complementary Index |
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