[Slides DEFENSE] Mapping Genotype to Phenotype using Attribute Grammar
MAPPING GENOTYPE TO PHENOTYPE USING ATTRIBUTE GRAMMAR
Doctoral Dissertation Defense Thursday, July 25th, 2013 – 1:00PM Virginia Bioinformatics Institute – Room 325LAURA ADAM Genetics, Bioinformatics and Computational Biology Program ADVISORY COMMITTEE: Jean Peccoud (Chair) David Bevan, Harold Garner, François Képès, Naren Ramakrishnan, John Tyson
Abstract
Over the past 10 years, several synthetic biology research groups have proposed tools and domain-specific languages to help with the design of artificial DNA molecules. Community standards for exchanging data between these tools, such as the Synthetic Biology Open Language (SBOL), have been developed. It is increasingly important to be able to perform in silico simulation before the time and cost consuming wet lab realization of the constructs, which, as technology advances, also become in themselves more complex. By extending the concept of describing genetic expression as a language, we propose to model relations between genotype and phenotype using formal language theory. We use attribute grammars to extract context-dependent information from genetic constructs and compile them into mathematical models, possibly giving clues about their phenotypes. We provide examples in the field of synthetic biology to model famous genetic regulatory networks – the genetic toggle switch or repressilator – with Ordinary Differential Equations (ODEs). We also show this formalism can be used to output a discrete boolean model of the constructs. To show that it also has the potential to map natural genomes to systems biology models, we designed a Genotype-to-Phenotype (G2P) language for the cell cycle regulation of budding yeast. We implemented a demo of these concepts in GenoCAD, a Computer Assisted Design (CAD) software for synthetic biology. GenoCAD guides users from design to simulation. Users can either design constructs with the attribute grammars provided or define their own project-specific languages. Outputting the mathematical model of a genetic construct is performed by DNA compilation based on the attribute grammar specified; the design of new languages by users necessitated the generation on-the-fly of such attribute grammar based DNA compilers. We also considered the impact of our research and its potential dual-use issues. Indeed, after the design exploration is performed in silico, the next logical step is to synthesize the designed construct’s DNA molecule to build the construct in vivo. We implemented an algorithm to identify sequences of concern of any length that are specific to Select Agents and Toxins, helping to ensure safer use of our methods.
Related publications
Galdzicki, M., Wilson, M. L., Rodriguez, C. A., Pocock, M. R., Oberortner, E., Adam, L., … Sauro, H. M. (2012). Synthetic Biology Open Language (SBOL) Version 1.1.0, 1–26.
Wilson, M. L., Hertzberg, R., Adam, L., & Peccoud, J. (2011). A step-by-step introduction to rule-based design of synthetic genetic constructs using GenoCAD. (C. Voigt, Ed.)Methods in enzymology, 498, 173–88. doi:10.1016/B978-0-12-385120-8.00008-5
Cai, Y., Lux, M. W., Adam, L., & Peccoud, J. (2009). Modeling structure-function relationships in synthetic DNA sequences using attribute grammars. PLoS computational biology, 5(10), e1000529. doi:10.1371/journal.pcbi.1000529
Adam, L., Kozar, M., Letort, G., Mirat, O., Srivastava, A., Stewart, T., … Peccoud, J. (2011). Strengths and limitations of the federal guidance on synthetic DNA. Nature Biotechnology, 29(3), 208–210. doi:10.1038/nbt.1802