Synthetic chromosome arms function in yeast and generate phenotypic diversity by design

Jessica S. Dymond, Sarah M. Richardson, Candice E. Coombes, Timothy Babatz, Héloïse Muller, Narayana Annaluru, William J. Blake, Joy W. Schwerzmann, Junbiao Dai, Derek L. Lindstrom, Annabel C. Boeke, Daniel E. Gottschling, Srinivasan Chandrasegaran, Joel S. Bader, Jef D. Boeke

    Research output: Contribution to journalArticle

    Abstract

    Recent advances in DNA synthesis technology have enabled the construction of novel genetic pathways and genomic elements, furthering our understanding of system-level phenomena. The ability to synthesize large segments of DNA allows the engineering of pathways and genomes according to arbitrary sets of design principles. Here we describe a synthetic yeast genome project, Sc2.0, and the first partially synthetic eukaryotic chromosomes, Saccharomyces cerevisiae chromosome synIXR, and semi-synVIL. We defined three design principles for a synthetic genome as follows: first, it should result in a (near) wild-type phenotype and fitness; second, it should lack destabilizing elements such as tRNA genes or transposons; and third, it should have genetic flexibility to facilitate future studies. The synthetic genome features several systemic modifications complying with the design principles, including an inducible evolution system, SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution). We show the utility of SCRaMbLE as a novel method of combinatorial mutagenesis, capable of generating complex genotypes and a broad variety of phenotypes. When complete, the fully synthetic genome will allow massive restructuring of the yeast genome, and may open the door to a new type of combinatorial genetics based entirely on variations in gene content and copy number.

    Original languageEnglish (US)
    Pages (from-to)471-476
    Number of pages6
    JournalNature
    Volume477
    Issue number7365
    DOIs
    StatePublished - Sep 22 2011

    ASJC Scopus subject areas

    • General

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  • Cite this

    Dymond, J. S., Richardson, S. M., Coombes, C. E., Babatz, T., Muller, H., Annaluru, N., Blake, W. J., Schwerzmann, J. W., Dai, J., Lindstrom, D. L., Boeke, A. C., Gottschling, D. E., Chandrasegaran, S., Bader, J. S., & Boeke, J. D. (2011). Synthetic chromosome arms function in yeast and generate phenotypic diversity by design. Nature, 477(7365), 471-476. https://doi.org/10.1038/nature10403