Genomes by design

| Next-generation DNA sequencing has revealed the complete genome sequences of numerous organisms, establishing a fundamental and growing understanding of genetic variation and phenotypic diversity. Engineering at the gene, network and whole-genome scale aims to introduce targeted genetic changes both to explore emergent phenotypes and to introduce new functionalities. Expansion of these approaches into massively parallel platforms establishes the ability to generate targeted genome modifications, elucidating causal links between genotype and phenotype, as well as the ability to design and reprogramme organisms. In this Review, we explore techniques and applications in genome engineering, outlining key advances and defining challenges. Nature Reviews Genetics | AOP, published online 11 August 2015; doi:10.1038/nrg3956 R E V I E W S NATURE REVIEWS | GENETICS ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved routes to natural bioremediation and platforms for metabolic engineering. Owing to their relatively small genome sizes, well-described and malleable mechanisms of DNA repair, and fast reproduction rate, microbial genomes are favourable targets for genetic engineering. Genome sequencing and concurrent computational advances have established a knowledge base that now necessitates nucleotide resolution for functional genetic testing and reprogramming. A mutable, controllable genome is required to fully interrogate and manipulate the phenotype landscape. This Review is chiefly concerned with the rationale, technologies and applications of genome design. When coupled with next-generation sequencing (NGS), the iterative genome engineering process — design, build, test, evolve and learn — has become a powerful pipeline for the exploration of emergent and novel phenotypes. Nature Reviews | Genetics Fi tn es s Network engineering Genome engineering Evolution a Genotype space Photype Engineering