Total synthesis of genomes.

Abstract

The total synthesis of genomes is a bottom-up bioengineering approach which empowers synthetic biologists to investigate complex biological hypotheses and reprogramme cells with novel functions. A successful genome synthesis requires (i) an informed design, (ii) a tractable approach to replace genomic with synthetic DNA, and (iii) a troubleshooting strategy for design flaws. While enabled by the advent of in vitro DNA synthesis and kilobase-scale in vivo DNA assembly approaches, this review highlights recent advances in megabase-scale assembly technologies as well as the nucleotide-resolution mapping of genotype-phenotype relationships. Collectively, these synthetic genomic techniques have enabled the completion of rewritten prokaryotic genomes and eukaryotic chromosomes. Furthermore, we discuss next-generation innovations in ML-driven genome design applied toward ongoing genome synthesis projects, which combined with expedited assembly techniques promise to increase the functional sequence space of redesigned organisms.

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