We will introduce rather conservative changes to the genome sequence, initially deleting or relocating genomic features using strategies we feel, from first principles, are unlikely to reduce fitness significantly. At the same time, we will be introducing site-specific recombination sequences, allowing subsequent in vitro evolution of the yeast strains generated. This opens up a whole new dimension – not just one synthetic genome, but whole populations of synthetic genomes will be available for analysis and future study. The basic approach is to encode site-specific recombination sites at carefully chosen positions in the synthetic chromosomes that are not expected to have an effect on fitness upfront, but will enable in vitro evolution oor “SCRaMbLE” to “tell us” what is in fact dispensable when we transiently express the appropriate recombinase and select for the survivors.