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toyLIFE: a computational framework to study the multi-level organisation of the genotype-phenotype map.

Arias CF, Catalán P, Manrubia S, Cuesta JA - Sci Rep (2014)

Bottom Line: Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed.Here we introduce toyLIFE, a multi-level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges -remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks.The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps.

View Article: PubMed Central - PubMed

Affiliation: 1] Grupo Interdisciplinar de Sistemas Complejos (GISC), Madrid, Spain [2] Dept. Matemáticas, Universidad Carlos III de Madrid, Leganés, Madrid, Spain.

ABSTRACT
The genotype-phenotype map is an essential object to understand organismal complexity and adaptability. However, its experimental characterisation is a daunting task. Thus, simple models have been proposed and investigated. They have revealed that genotypes differ in their robustness to mutations; phenotypes are represented by a broadly varying number of genotypes, and simple point mutations suffice to navigate the space of genotypes while maintaining a phenotype. Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed. Here we introduce toyLIFE, a multi-level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges -remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks. The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps.

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Related in: MedlinePlus

Dynamics of toyLIFE.Input molecules at time step t are toyProteins (Ps) (including toyDimers (Ds)) and toyMetabolites, either produced as output at time step t − 1 or environmentally supplied (all toyMetabolites denoted Ms). Ps and Ds interact with Ms to produce complexes P-M and D-M. Next, these complexes, the remaining Ps and Ds, and the toyPolymerase (Pol) interact with toyGenes (G) at the regulation phase. The most stable complexes with promoters are formed (Pol-G, P-G and D-G), activating or inhibiting toyGenes. P-Ms and D-Ms do not participate in regulation. Ps and Ds not in complexes are eliminated and new Ps (dark grey) are formed. These Ps interact with all molecules present and form Ds, new P-M and D-M complexes, and catabolise old D-M complexes. At the end of this phase, all Ms not bound to Ps or Ds are returned to the environment, and all Ps and Ds in P-M and D-M complexes unbind and are degraded. The remaining molecules (Ms just released from complexes, as well as all free Ps and Ds) go to the input set of time step t + 1.
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f3: Dynamics of toyLIFE.Input molecules at time step t are toyProteins (Ps) (including toyDimers (Ds)) and toyMetabolites, either produced as output at time step t − 1 or environmentally supplied (all toyMetabolites denoted Ms). Ps and Ds interact with Ms to produce complexes P-M and D-M. Next, these complexes, the remaining Ps and Ds, and the toyPolymerase (Pol) interact with toyGenes (G) at the regulation phase. The most stable complexes with promoters are formed (Pol-G, P-G and D-G), activating or inhibiting toyGenes. P-Ms and D-Ms do not participate in regulation. Ps and Ds not in complexes are eliminated and new Ps (dark grey) are formed. These Ps interact with all molecules present and form Ds, new P-M and D-M complexes, and catabolise old D-M complexes. At the end of this phase, all Ms not bound to Ps or Ds are returned to the environment, and all Ps and Ds in P-M and D-M complexes unbind and are degraded. The remaining molecules (Ms just released from complexes, as well as all free Ps and Ds) go to the input set of time step t + 1.

Mentions: The dynamics of the model proceeds in discrete time steps and variable molecular concentrations are not taken into account. A step-by-step description of toyLIFE dynamics is summarised in Figure 3. There is an initial set of molecules which results from the previous time step: toyProteins (including toyDimers and the toyPolymerase) and toyMetabolites, either endogenous or provided by the environment. These molecules first interact between them to form possible complexes (see previous section) and are then presented to a collection of toyGenes that is kept constant along subsequent iterations. Regulation takes place, mediated by a competition for binding the promoters of toyGenes, possibly causing their activation and leading to the formation of new toyProteins. Binding to promoters is decided in sequence. Starting with any of them (the order is irrelevant), it is checked whether any of the toyProteins/toyDimers available bind to the promoter —remember that complexes bound to toyMetabolites are not available for regulation—, and then whether the toyPolymerase can subsequently bind to the complex and express the accompanying coding region. If it does, the toyGene is marked as active and the toyProtein/toyDimer is released. Then a second promoter is chosen and the process repeated, until all promoters have been evaluated. toyGenes are only expressed after all of them have been marked as either active or inactive. Each expressed toyGene produces one single toyProtein molecule. There can be more units of the same toyProtein, but only if multiple copies of the same toyGene are present.


toyLIFE: a computational framework to study the multi-level organisation of the genotype-phenotype map.

Arias CF, Catalán P, Manrubia S, Cuesta JA - Sci Rep (2014)

Dynamics of toyLIFE.Input molecules at time step t are toyProteins (Ps) (including toyDimers (Ds)) and toyMetabolites, either produced as output at time step t − 1 or environmentally supplied (all toyMetabolites denoted Ms). Ps and Ds interact with Ms to produce complexes P-M and D-M. Next, these complexes, the remaining Ps and Ds, and the toyPolymerase (Pol) interact with toyGenes (G) at the regulation phase. The most stable complexes with promoters are formed (Pol-G, P-G and D-G), activating or inhibiting toyGenes. P-Ms and D-Ms do not participate in regulation. Ps and Ds not in complexes are eliminated and new Ps (dark grey) are formed. These Ps interact with all molecules present and form Ds, new P-M and D-M complexes, and catabolise old D-M complexes. At the end of this phase, all Ms not bound to Ps or Ds are returned to the environment, and all Ps and Ds in P-M and D-M complexes unbind and are degraded. The remaining molecules (Ms just released from complexes, as well as all free Ps and Ds) go to the input set of time step t + 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269896&req=5

f3: Dynamics of toyLIFE.Input molecules at time step t are toyProteins (Ps) (including toyDimers (Ds)) and toyMetabolites, either produced as output at time step t − 1 or environmentally supplied (all toyMetabolites denoted Ms). Ps and Ds interact with Ms to produce complexes P-M and D-M. Next, these complexes, the remaining Ps and Ds, and the toyPolymerase (Pol) interact with toyGenes (G) at the regulation phase. The most stable complexes with promoters are formed (Pol-G, P-G and D-G), activating or inhibiting toyGenes. P-Ms and D-Ms do not participate in regulation. Ps and Ds not in complexes are eliminated and new Ps (dark grey) are formed. These Ps interact with all molecules present and form Ds, new P-M and D-M complexes, and catabolise old D-M complexes. At the end of this phase, all Ms not bound to Ps or Ds are returned to the environment, and all Ps and Ds in P-M and D-M complexes unbind and are degraded. The remaining molecules (Ms just released from complexes, as well as all free Ps and Ds) go to the input set of time step t + 1.
Mentions: The dynamics of the model proceeds in discrete time steps and variable molecular concentrations are not taken into account. A step-by-step description of toyLIFE dynamics is summarised in Figure 3. There is an initial set of molecules which results from the previous time step: toyProteins (including toyDimers and the toyPolymerase) and toyMetabolites, either endogenous or provided by the environment. These molecules first interact between them to form possible complexes (see previous section) and are then presented to a collection of toyGenes that is kept constant along subsequent iterations. Regulation takes place, mediated by a competition for binding the promoters of toyGenes, possibly causing their activation and leading to the formation of new toyProteins. Binding to promoters is decided in sequence. Starting with any of them (the order is irrelevant), it is checked whether any of the toyProteins/toyDimers available bind to the promoter —remember that complexes bound to toyMetabolites are not available for regulation—, and then whether the toyPolymerase can subsequently bind to the complex and express the accompanying coding region. If it does, the toyGene is marked as active and the toyProtein/toyDimer is released. Then a second promoter is chosen and the process repeated, until all promoters have been evaluated. toyGenes are only expressed after all of them have been marked as either active or inactive. Each expressed toyGene produces one single toyProtein molecule. There can be more units of the same toyProtein, but only if multiple copies of the same toyGene are present.

Bottom Line: Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed.Here we introduce toyLIFE, a multi-level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges -remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks.The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps.

View Article: PubMed Central - PubMed

Affiliation: 1] Grupo Interdisciplinar de Sistemas Complejos (GISC), Madrid, Spain [2] Dept. Matemáticas, Universidad Carlos III de Madrid, Leganés, Madrid, Spain.

ABSTRACT
The genotype-phenotype map is an essential object to understand organismal complexity and adaptability. However, its experimental characterisation is a daunting task. Thus, simple models have been proposed and investigated. They have revealed that genotypes differ in their robustness to mutations; phenotypes are represented by a broadly varying number of genotypes, and simple point mutations suffice to navigate the space of genotypes while maintaining a phenotype. Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed. Here we introduce toyLIFE, a multi-level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges -remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks. The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps.

Show MeSH
Related in: MedlinePlus