Genetics from scratch: Designing and building synthetic eukaryotic chromosomes

摘要

Designing and building non-native DNA sequences conferring specific and useful engineered functions on cells defines the field of synthetic biology. With the decreasing cost of gene synthesis, ready 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. Saccharomyces cerevisiae, a model organism highly amenable to genetic manipulation and an industrial workhorse, is an excellent platform to develop tools for eukaryotic chromosome and genome engineering. We have developed new approaches to assemble and manipulate designer synthetic chromosomes for expression in S. cerevisiae. This includes the combinatorial assembly of nonnative pathways [1, 2] and the `telomerator', a tool to induce chromosome linearization and specify gene order and orientation [3]. We now aim to build the world's first designer eukaryotic genome, Sc2.0, through the combined efforts of an international consortium [4, 5]. Moving forward, application of these approaches to writing mammalian chromosomes and genomes is a major goal. We are working to enable design, assembly, delivery, and evaluation of synthetic mammalian designer gene loci in cell culture and animals.