In the future, entire genomes tailored to specific functions and environments could be designed using computational tools. However, computational tools to design cells are scarce. Here we present work implementing computational design-simulate-test cycles for genome optimisation based on whole cell modelling. Similar approaches could be adapted to any goal in genome design, but to demonstrate feasibility, we selected the identification of minimal genomes as a proof of concept, using the first (and currently only published) whole cell model, which is for the bacterium Mycoplasma genitalium . Minimal genomes are an ideal goal to test our ideas because there is a very simple functional assay -the cell can either replicate or not. Our computational design-simulate-test cycles produced novel in-silico minimal genomes smaller than JCVI-Syn3.0 , the smallest genome ever synthesised in the lab, and identified 11 redundant essential genes. This work brings computational genome design a step closer.

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