Genetics from scratch: designing and building synthetic eukaryotic chromosomes

With the decreasing cost of gene synthesis, availability of genome sequence data, and new DNA assembly strategies, we are now in a position to build designer chromosomes from scratch. Applying a ‘bottom-up’ genetics approach enables new research questions that can both test and extend our knowledge of chromosome and genome biology. I will describe new approaches to assemble and manipulate designer synthetic chromosomes for expression in S. cerevisiae, including the combinatorial assembly of non-native pathways onto supernumerary chromosomes, the ‘telomerator’ as a tool to specify gene order and orientation, and the Synthetic Yeast Genome Project, Sc2.0, aiming to build the world’s first synthetic eukaryotic genome encoding myriad designer changes. Together this work serves a platform for systematic studies of eukaryotic chromosomes, opening up new large-scale capabilities and opportunities for designed genomes.