From Minimal to Minimized Genomes: Functional Design of Microbial Cell Factories

The minimal genome is a theoretical concept asking what is the minimal gene set that defines life under a given environment. Experimental efforts show that stripping off most non-essential genes results in fragile organisms with “minimal genomes”. By contrast, eliminating cryptic genes and mobile DNA results in strains with “minimized genomes” suitable for biotechnological applications because they display enhanced productivity, robust growth and upscalability. While it is believed that a minimal genome could be used to plug in “metabolic modules”, we argue that there is no universal “chassis” because different organisms are suited to different environments. A further issue with the minimal genome is that it places DNA at the top of the hierarchy that led to the origin of life, ignoring metabolism and supporting a gene-centric view of evolution. This hardly accommodates the fact that the invention of nucleotides must have been a late event in prebiotic evolution. In this work, we take a “metabolism first” approach to describe the emergence of the first cells and the evolution of selected metabolic pathways that provided different solutions to the same problem. Understanding such processes provides insights for developing platform strains in metabolic engineering and industrial biotechnology.