Designing minimal genomes using whole-cell models

Joshua Rees-Garbutt, Oliver Chalkley, Sophie Landon, Oliver Purcell, Lucia Marucci () and Claire Grierson ()
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Joshua Rees-Garbutt: University of Bristol
Oliver Chalkley: University of Bristol
Sophie Landon: University of Bristol
Oliver Purcell: Engine Biosciences, MBC Biolabs
Lucia Marucci: University of Bristol
Claire Grierson: University of Bristol

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract In the future, entire genomes tailored to specific functions and environments could be designed using computational tools. However, computational tools for genome design are currently scarce. Here we present algorithms that enable the use of design-simulate-test cycles for genome design, using genome minimisation as a proof-of-concept. Minimal genomes are ideal for this purpose as they have a simple functional assay whether the cell replicates or not. We used the first (and currently only published) whole-cell model for the bacterium Mycoplasma genitalium. Our computational design-simulate-test cycles discovered novel in silico minimal genomes which, if biologically correct, predict in vivo genomes smaller than JCVI-Syn3.0; a bacterium with, currently, the smallest genome that can be grown in pure culture. In the process, we identified 10 low essential genes and produced evidence for at least two Mycoplasma genitalium in silico minimal genomes. This work brings combined computational and laboratory genome engineering a step closer.

Date: 2020
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DOI: 10.1038/s41467-020-14545-0

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