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Modeling structure-function relationships in synthetic DNA sequences using attribute grammars.

Cai Y, Lux MW, Adam L, Peccoud J - PLoS Comput. Biol. (2009)

Bottom Line: Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part.They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts.This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology.

View Article: PubMed Central - PubMed

Affiliation: Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.

ABSTRACT
Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part. This concept provides a finer level of granularity than the traditional notion of the gene. However, a method of formally relating how a set of parts relates to a function has not yet emerged. Synthetic biology both demands such a formalism and provides an ideal setting for testing hypotheses about relationships between DNA sequences and phenotypes beyond the gene-centric methods used in genetics. Attribute grammars are used in computer science to translate the text of a program source code into the computational operations it represents. By associating attributes with parts, modifying the value of these attributes using rules that describe the structure of DNA sequences, and using a multi-pass compilation process, it is possible to translate DNA sequences into molecular interaction network models. These capabilities are illustrated by simple example grammars expressing how gene expression rates are dependent upon single or multiple parts. The translation process is validated by systematically generating, translating, and simulating the phenotype of all the sequences in the design space generated by a small library of genetic parts. Attribute grammars represent a flexible framework connecting parts with models of biological function. They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts. This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology.

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Parse tree showing the derivation process of a two-cassette genetic construct.In the derivation tree, terms in <> corresponds to the non-terminals in the grammar, while terms in [ ] are terminals, and the dashed lines indicate the transformation to terminals. The subscripts are used to distinguish different instances of the same category.
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pcbi-1000529-g002: Parse tree showing the derivation process of a two-cassette genetic construct.In the derivation tree, terms in <> corresponds to the non-terminals in the grammar, while terms in [ ] are terminals, and the dashed lines indicate the transformation to terminals. The subscripts are used to distinguish different instances of the same category.

Mentions: The translation of a gene network model from a genetic sequence is very similar to the compilation of the source code of a computer program into an object code that can be executed by a microprocessor (Figure 1). The first step consists in breaking down the DNA sequence into a series of genetic parts by a program called the lexer or scanner. Since the sequence of a part may be contained in the sequence of another part, the lexer is capable of backtracking to generate all the possible interpretations of the input DNA sequences as a series of parts. All possible combinations of parts generated by the lexer are sent to a second program called the parser to analyze if they are structurally consistent with the language syntax. The structure of a valid series of parts is represented by a parse tree [50] (Figure 2). The semantic evaluation takes advantage of the parse tree to translate the DNA sequence into a different representation such as a chemical reaction network. The translation process requires attributes and semantic actions. Attributes are properties of individual genetic parts or combinations of parts. Semantic actions are associated with the grammar production rules. They specify how attributes are computed. Specifically, the translation process relies on the semantic actions associated with parse tree nodes to synthesize the attributes of the construct from the attributes of its child nodes, or to inherit the attributes from its parental node. In our implementation, the product of the translation is a mass action model of the network of molecular interactions encoded in the DNA sequence. By using the standardized format of Systems Biology Markup Language (SBML), the model can be analyzed using existing simulation engines [58]–[60].


Modeling structure-function relationships in synthetic DNA sequences using attribute grammars.

Cai Y, Lux MW, Adam L, Peccoud J - PLoS Comput. Biol. (2009)

Parse tree showing the derivation process of a two-cassette genetic construct.In the derivation tree, terms in <> corresponds to the non-terminals in the grammar, while terms in [ ] are terminals, and the dashed lines indicate the transformation to terminals. The subscripts are used to distinguish different instances of the same category.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2748682&req=5

pcbi-1000529-g002: Parse tree showing the derivation process of a two-cassette genetic construct.In the derivation tree, terms in <> corresponds to the non-terminals in the grammar, while terms in [ ] are terminals, and the dashed lines indicate the transformation to terminals. The subscripts are used to distinguish different instances of the same category.
Mentions: The translation of a gene network model from a genetic sequence is very similar to the compilation of the source code of a computer program into an object code that can be executed by a microprocessor (Figure 1). The first step consists in breaking down the DNA sequence into a series of genetic parts by a program called the lexer or scanner. Since the sequence of a part may be contained in the sequence of another part, the lexer is capable of backtracking to generate all the possible interpretations of the input DNA sequences as a series of parts. All possible combinations of parts generated by the lexer are sent to a second program called the parser to analyze if they are structurally consistent with the language syntax. The structure of a valid series of parts is represented by a parse tree [50] (Figure 2). The semantic evaluation takes advantage of the parse tree to translate the DNA sequence into a different representation such as a chemical reaction network. The translation process requires attributes and semantic actions. Attributes are properties of individual genetic parts or combinations of parts. Semantic actions are associated with the grammar production rules. They specify how attributes are computed. Specifically, the translation process relies on the semantic actions associated with parse tree nodes to synthesize the attributes of the construct from the attributes of its child nodes, or to inherit the attributes from its parental node. In our implementation, the product of the translation is a mass action model of the network of molecular interactions encoded in the DNA sequence. By using the standardized format of Systems Biology Markup Language (SBML), the model can be analyzed using existing simulation engines [58]–[60].

Bottom Line: Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part.They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts.This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology.

View Article: PubMed Central - PubMed

Affiliation: Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.

ABSTRACT
Recognizing that certain biological functions can be associated with specific DNA sequences has led various fields of biology to adopt the notion of the genetic part. This concept provides a finer level of granularity than the traditional notion of the gene. However, a method of formally relating how a set of parts relates to a function has not yet emerged. Synthetic biology both demands such a formalism and provides an ideal setting for testing hypotheses about relationships between DNA sequences and phenotypes beyond the gene-centric methods used in genetics. Attribute grammars are used in computer science to translate the text of a program source code into the computational operations it represents. By associating attributes with parts, modifying the value of these attributes using rules that describe the structure of DNA sequences, and using a multi-pass compilation process, it is possible to translate DNA sequences into molecular interaction network models. These capabilities are illustrated by simple example grammars expressing how gene expression rates are dependent upon single or multiple parts. The translation process is validated by systematically generating, translating, and simulating the phenotype of all the sequences in the design space generated by a small library of genetic parts. Attribute grammars represent a flexible framework connecting parts with models of biological function. They will be instrumental for building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts. This formalism is also expected to provide a solid foundation for the development of computer assisted design applications for synthetic biology.

Show MeSH
Related in: MedlinePlus