Scientists enjoy unprecedented access to custom genetic constructs through synthetic biology. The cost of gene synthesis falls and efficiency rises—encouraging a shift from gene and pathway synthesis to whole genome synthesis. Chemically synthesized genomes are customizable, offering researchers a chance to test otherwise intractable hypotheses about chromosome structure, function, and evolution. Tools for the design of synthetic constructs are not widely available, however, and even when available are rarely open source. In addition, the larger-scale problems of computer-assisted chromosome and genome design remain entirely unaddressed. Practitioners currently either edit sequence by hand or press smaller design tools into awkward service. An optimal genome design framework would allow a team of designers to make coordinated modifications to sequence at both the base pair and the genome scale, to track changes, and to roll back changes at multiple scales. This dissertation discusses G ENEDESIGN and BIOSTUDIO, two suites of algorithms for gene and genome design that seek to address those major goals of team-based synthetic design. Although both GENED ESIGN and BIOSTUDIO are organism-agnostic, their implementation is described in the context of the design and synthesis of synthetic genes and chromosomes for Saccharornyces cerevisiae 2.0. The goal of the Sc2.0 project is the complete synthesis of a re-designed genome for baker's yeast. The resulting organism will permit systematic studies of eukaryotic chromosome structure that have been impossible to explore with traditional gene-at-a-time experiments. The efficiency of chemical synthesis of DNA does not currently permit direct synthesis of an entire prokaryotic chromosome, let alone a eukaryotic genome. However, it is feasible to synthesize multi-kilobase pieces of DNA and combine them into larger molecules, a task that is usually accomplished by biological experts manually, in a laborious and error-prone fashion. BIOSTUDIO approaches DNA design as an optimization problem and generates chromosome designs that can be assembled from the bottom-up to facilitate troubleshooting. Both G ENEDESIGN and BIOSTUDIO are implemented in Perl and are freely available under the new BSD license. This work was supported by funding from the Department of Energy, grant number DE-FG02097ER25308.
|Advisor:||Bader, Joel S.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 74/01(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Systematic, Bioinformatics|
|Keywords:||Genome design, Synthetic biology|
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