Designing Minimal Genomes Using Whole-Cell Models

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 very simple functional assay, the cell can either replicate or not. We used the first (and currently only published) whole-cell model, for the bacterium Mycoplasma genitalium 1. Our computational design-simulate-test cycles discovered novel in-silico minimal genomes smaller than JCVI-Syn3.0 2, a bacterial cell with the currently known smallest genome that can be grown in pure culture. In the process, we identified 10 low essentiality genes, 18 high essentiality genes 3, and produced evidence for at least two minimal genomes for Mycoplasma genitalium in-silico. This work brings combined computational and laboratory genome design and construction a step closer.