Daniel T Lusk, Ian M Ehrenreich
A central goal of biology is to understand how genome sequence, content and organization give rise to living systems with specific traits. Achieving this goal requires understanding which genes are collectively required for life and for particular traits, how their products work together and how the organization of these genes in the genome affects cellular function. At a broader scale, it also means determining the mechanisms that generate inherited phenotypic diversity and enable adaptation and speciation. Synthetic chromosome assembly in the budding yeast Saccharomyces cerevisiae provides a tractable platform for probing these relationships in a model eukaryote by allowing chromosomes to be designed, built and tested directly in living cells. By making chromosome-scale genome architecture an experimental variable, chromosome synthesis differs from approaches that describe organisms as they occur in nature or test the effects of one or a few genes at a time. This review traces the emergence of yeast synthetic chromosomes as tools for genome biology and identifies advances needed to make chromosome-scale design more predictive.