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The falling cost of DNA synthesis and the increasing breadth of genomic datasets have prompted the question -- is it possible to design and build a working genome from scratch? The ability to order and assemble whole genomic sequences will give us the capacity to explore specific hypotheses on the genome-scale.
The successful design and deployment of any synthetic genome project entails solving three major problems. First, manipulations that are simple enough to be accomplished by manual editing at the gene-scale become unreasonably involved if done by hand at the genome-scale. Second, it is currently extremely difficult to accurately synthesize long strands of DNA in a volume appropriate for cell transplantation. This leaves the synthetic biologist with two options for a synthetic genome -- in vivo manipulations, or in vitro assembly of large stretches of genome from smaller oligos followed by cellular integration. Third, as the project progresses there will be many versions of the synthetic genome actualized, which must each be carefully annotated and tracked to allow a "roll-back" in the case of lethal modifications.
My group is working on the creation of a synthetic Saccharomyces cerevisiae-based genome, and we have begun to address each of the above issues. I am currently working on the problem of computer-assisted design of synthetic genomes. Computational assistance is required for multikilobase sequence analysis annotation, but there are few tools available that are appropriate for the tasks of synthetic design. The successful assembly of a synthetic genome requires very careful planning and editing during the design phase, and an algorithm that automates these tasks for a eukaryotic genome should be an interesting and useful algorithm to generalize for any kilobase-scale synthetic project.
Richardson SM, Wheelan SJ, Yarrington RM, and Boeke JD. GeneDesign: rapid, automated design of multikilobase synthetic genes. Genome Res. 2006 16, 550-6
Dymond J, Scheifele L, Richardson S, Lee P, Chandrasegaran S, Bader J, and Boeke JD. Teaching Synthetic Biology, Bioinformatics, and Engineering to Undergraduates: The Interdisciplinary Build-a-Genome Course. Genetics 2009 181, 13--21
Richardson SM, Olson BS, Dymond JS, Burns R, Chandrasegaran S, Boeke JD, Shehu A, and Bader JS. Automated Design of Assemblable, Modular, Synthetic Chromosomes. LNCS, in press.
Richardson SM, Nunley PW, Yarrington RM, Boeke JD, and Bader JS. GeneDesign 3.0 is an Updated Synthetic Biology Toolkit. Nucleic Acids Res 2010 38, 2603-2606
Lee PA, Dymond JS, Scheifele LZ, Richardson SM, Foelber KJ, Boeke JD, and Bader JS. CLONEQC: lightweight sequence verification for synthetic biology. Nucleic Acids Res 2010 38, 2617-2623
Yarrington RM, Richardson SM, and Boeke JD. Novel expression inhibiting-function of exon-binding Rap1p revealed by synthetic codon-optimized Ty1 retrotransposon. submitted.
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