4.1  Synthetic yeast genomes
A key early advantage in synthetic yeast genome design was enabled by Saccharomyces cerevisiae ’s well-curated and regularly updated genome sequence (Cherry et al., 2012). This in turn enabled synthetic genome designers the ability to rapidly derive value and understanding by implementing a ‘build-to-understand’ approach through the construction of a synthetic yeast genome. The starting material of this synthetic yeast genome was founded on the haploid laboratory strain, S. cerevisiae S288c and associated ‘BY’ lineage, with the end goal to ultimately design and chemically synthesize a modified version (Richardson et al., 2017).
At the beginning of the previous decade, the availability of this well-characterised reference genome sparked the idea of swapping the natural genome of S. cerevisiae S288c with a redesigned and chemically synthesized version without compromising the physiological fitness of the original host strain (Dymond et al., 2011). In 2019, the work of an international Synthetic Yeast Genome (Yeast 2.0 or Sc2.0) consortium culminated in the announcement of the first draft synthetic set of the 16 linear chromosomes of the ‘BY’ lineage (Pretorius, 2020). However, since the 2019 announcement, several of these draft chromosomes still needed to be corrected for growth defects. With the exception of one chromosome, the ‘debugging’ is now complete and the publications are currently under review. It is anticipated that the sequential consolidation of synthetic chromosomes into a single cell will accelerate progress toward the ultimate Sc2.0 strain, which will ultimately contain a radically altered genome. This includes streamlining and stabilising (removal of transposons, non-essential introns; and the relocation of all tRNA genes onto a separate, supernumerary tRNA neochromosome), addition of standardised telomeres, a ‘freed-up’ TGA stop codon, PCR-Tags recognition labels and multiple LoxPsym sites (Richardson et al., 2017).