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• W4386034495 abstract "GEN BiotechnologyVol. 2, No. 4 Views & NewsFree AccessDeciphering the Evolutionary Adaptations of Life with a Minimal GenomeFankang Meng and Tom EllisFankang MengImperial College Centre for Synthetic Biology, Imperial College London, London, United Kingdom; and Imperial College London, London, United Kingdom.Department of Bioengineering, Imperial College London, London, United Kingdom.Search for more papers by this author and Tom Ellis*Address correspondence to: Tom Ellis, Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom, E-mail Address: [email protected]Imperial College Centre for Synthetic Biology, Imperial College London, London, United Kingdom; and Imperial College London, London, United Kingdom.Department of Bioengineering, Imperial College London, London, United Kingdom.Search for more papers by this authorPublished Online:17 Aug 2023https://doi.org/10.1089/genbio.2023.29108.fmeAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail A new report in Nature shows that bacteria with minimal synthetic genomes demonstrate an unexpected ability to adapt by evolution, despite having half their normal gene content removed.Advances in synthetic biology have enabled the design and construction of minimal cells whose genomes only contain the essential genes required for life in the laboratory. But if you strip genomes down to the bare minimum—just the essential genes that cannot be deleted—then does this make it harder for cells to survive mutations to their DNA and to adapt and evolve? Writing in Nature, Roy Moger-Reischer, Jay Lennon and colleagues sought to answer this question by studying the laboratory-based evolution of synthetic strains of Mycoplasma mycoides, specifically a strain with a minimized genome, JCVI-syn3B, and a strain with the full genome, JCVI-syn1.0.1JCVI-syn3B is a derivative of the smallest known free-living organism, JCVI-syn3.0.2 In prior work, Clyde Hutchinson and colleagues from the J. Craig Venter Institute systematically removed almost half of the original 901 genes present in the genome of the nonminimal JCVI-syn1.0,3 leaving only 473 genes in JCVI-syn3.0. JCVI-syn3B has undergone further modifications, including the reintroduction of 19 genes and the integration of a Cre-loxP-based landing pad into the genome, making it easier to utilize for laboratory research.4,5 JCVI-syn3B provides a unique opportunity as a strain for experiments that look for a deeper understanding of the implications of genome minimization and what impact “streamlining” a genome has on an organism's ability to adapt and evolve.In the new study, Moger-Reischer et al. first investigated whether genome streamlining altered the mutation rate in the minimal genome compared with the nonminimal genome. Strikingly, they found that the mutation rates were virtually indistinguishable between the two cell types, even though genome streamlining involved removal of genes associated with replication fidelity. However, despite the constant overall mutation rate, there was an effect on the types of mutations that occurred. An A:T bias was accentuated in the minimal cell, perhaps due to the deletion of the ung gene that prevents C-to-T mutations from misincorporated uracil.Next, they evaluated how streamlining affected adaptation over 2000 generations of experimental evolution in laboratory cultures. Notably, JCVI-syn3B rapidly regained fitness and even adapted more rapidly than JCVI-syn1.0, despite the genome streamlining having previously led to the minimal cell having <50% of the fitness of the nonminimal cell. The final relative fitness of the evolved minimal cell was statistically indistinguishable from that of the ancestral nonminimal cell, implying that genome streamlining did not restrict adaptability. The evolution of cell size, however, did exhibit a noticeable constraint. Although the nonminimal cell's size expanded by 80%, the minimal cell maintained its size (Fig. 1).FIG. 1. The effect of genome minimization and evolution on cellular fitness.The relative sizes of the circles in the diagram indicates the change in cell diameter after genome streamlining or evolution. Dots within the circles correspond to the number of genes in the respective genomes.Through statistical simulation and reverse genetics, key mutations contributing to these adaptive patterns were identified. Diverse sets of essential genes were found to acquire mutations in both cell types, suggesting divergent routes of evolution. For example, the researchers detected a marginal signal of enrichment for mutations in biosynthetic genes of the minimal cell. A possible shift in metabolic pathways toward lipid synthesis and distribution appeared to be a more critical factor for the minimal cell.The authors next looked in detail at the effects of genome streamlining and evolution on one important yet easy-to-measure phenotype—cell size. They found that a mutation in the ftsZ gene that introduces an early stop codon led to opposing outcomes on the size of minimal and nonminimal cells. In the case of the nonminimal cell, the mutation led to a 25% increase in cell diameter and a doubling of cell volume. Conversely, the identical ftsZ mutation in the minimal cell led to a 19% decrease in cell diameter, halving the cell volume.Yet, the mutation increased fitness in both cell types, by 25% in nonminimal and 14% in minimal cells. The researchers posit that cell size, tied to multiple genes, could evolve under direct selective pressures or indirectly through selection of other traits, highlighting the intricate relationship between cell size, evolutionary fitness, and genomic context.Overall, this study has advanced our understanding of genome streamlining. Although the minimal genome lacks the genetic redundancy commonly associated with adaptability, streamlining did not seem to constrain fitness evolution and diversification over time. This is a particularly encouraging result for those working toward a future where minimal synthetic genomes are designed for cells to be self-replicating technologies that do dedicated tasks, like cell therapy, pollution remediation, or materials production.6If the results with JCVI-syn3B are generalizable to other bacteria and eukaryotic genomes too, then it appears that minimizing a genome is more of an opportunity than has been previously expected. Streamlining genomes does not have to lead to “fragile” cells, nor is it a barrier for then using evolution to optimize for better performance. Not only can we use evolution to gain new knowledge on genome biology and useful genome edits,7 but we can also use it to optimize synthetic designs and constructed genomes to make them more efficient and robust in diverse scenarios.8,9References1. Moger-Reischer RZ, Glass JI, Wise KS, et al. Evolution of a minimal cell. Nature 2023; doi: 10.1038/s41586-023-06288-x Crossref, Google Scholar2. Hutchison C, Chuang R, Noskov V, et al. Design and synthesis of a minimal bacterial genome. Science 2016;351(6280):aad6253; doi: 10.1126/science.aad6253 Crossref, Medline, Google Scholar3. Gibson DG, Glass J, Lartigue C, et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science 2010;329(5987):52–56; doi: 10.1126/science.1190719 Crossref, Medline, Google Scholar4. Bittencourt DM de C, Brown DM, Assad-Garcia N, et al. Minimal cell JCVI-syn3B as a chassis to reveal the mechanisms behind Mycoplasma host–pathogen interactions. SSRN Electron J 2022; doi: 10.2139/ssrn.4234690 Crossref, Google Scholar5. Breuer M, Earnest TM, Merryman C, et al. Essential metabolism for a minimal cell. Elife 2019;8:e36842; doi: 10.7554/elife.36842 Crossref, Medline, Google Scholar6. Xu X, Meier F, Blount BA, et al. Trimming the genomic fat: Minimising and re-functionalising genomes using synthetic biology. Nat Commun 2023;14(1):1984; doi: 10.1038/s41467-023-37748-7 Crossref, Medline, Google Scholar7. Nissan RB, Milshtein E, Pahl V, et al. Autotrophic growth of E. coli is achieved by a small number of genetic changes. bioRxiv 2023; doi: 10.1101/2023.06.03.543535 Crossref, Google Scholar8. Bozdag GO, Zamani-Dahaj SA, Day TC, et al. De novo evolution of macroscopic multicellularity. Nature 2023;1–8; doi: 10.1038/s41586-023-06052-1 Crossref, Google Scholar9. Castle SD, Grierson CS, Gorochowski TE. Towards an engineering theory of evolution. Nat Commun 2021;12(1):3326; doi: 10.1038/s41467-021-23573-3 Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 2Issue 4Aug 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Fankang Meng and Tom Ellis.Deciphering the Evolutionary Adaptations of Life with a Minimal Genome.GEN Biotechnology.Aug 2023.285-286.http://doi.org/10.1089/genbio.2023.29108.fmePublished in Volume: 2 Issue 4: August 17, 2023PDF download" @default.
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