Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. They have also enabled the construction of novel genetic pathways and genomic elements, furthering our understanding of systems-level phenomena. The synthetic yeast genome project, Sc2.0 is well on its way with several of the first synthetic Saccharomyces cerevisiae chromosomes completed. Undergraduate students provide a workforce for synthesis and assembly for some of these chromosomes, though a wide variety of assembly schemes are employed by the various groups building chromosomes. The synthetic genome features several systemic modifications, including TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, tRNA genes, transposons and silent mating loci as well as strategically placed loxPsym sites to enable genome scrambling using an inducible evolution system termed SCRaMbLE (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution). SCRaMbLE can be used as a novel method of mutagenesis, capable of generating complex genotypes and a variety of phenotypes. The fully synthetic yeast genome will open the door to a new type of combinatorial genetics based on variations in gene content and copy number, rather than base changes. We also describe supernumerary designer “neochromosomes” that add new functionalities to cells such as humanized pathways. Now, even larger genome synthesis projects can be contemplated.
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