Limits...
Latent phenotypes pervade gene regulatory circuits.

Payne JL, Wagner A - BMC Syst Biol (2014)

Bottom Line: Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit's main functions.Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes.Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Zurich, Zurich, Switzerland. andreas.wagner@ieu.uzh.ch.

ABSTRACT

Background: Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations.

Results: Here, we study a space of more than sixteen million three-gene model regulatory circuits, where each circuit is represented by a genotype, and has one or more functions embodied in one or more gene expression phenotypes. We find that the majority of circuits with single functions have latent expression phenotypes. Moreover, the set of circuits with a given spectrum of functions has a repertoire of latent phenotypes that is much larger than that of any one circuit. Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit's main functions. Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes.

Conclusions: Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation.

Show MeSH
Schematic illustration of a Boolean circuit.(A) Each circuit has N=3 genes, shown as labeled open circles (a,b,c). Genes can be in one of two states: expressed (1) or not expressed (0). Regulatory interactions are depicted as directed edges a→b, which indicate that the gene product of a regulates the expression of b. The signal-integration logic of each gene is captured in a lookup table, where each entry encodes the gene’s regulatory response to one of the 2N possible combinations of the states of its regulating gene products. These lookup tables also specify the circuit’s wiring diagram. For example, the expression of gene a is independent of gene c because its lookup table specifies the Boolean logic function “a and b.” The regulatory interaction c→a is thus inactive, as indicated by the gray color of this edge. (B) By concatenating the rightmost columns of each lookup table, the signal-integration logic and wiring diagram of a circuit can be represented as a single vector G of length L = N × 2N. We consider G to be the circuit’s genotype. (C) The circuit shown in panel (A) is a member of the genotype set of the bifunction F(1):〈0,0,0〉↦〈0,0,0〉, F(2):〈0,0,1〉↦〈0,1,0〉. (D) Each circuit with a given multifunction may map initial states that are not part of the multifunction to new equilibrium states. We consider these to be latent phenotypes. For example, of the five states that are not part of the multifunction shown in (C), three map to the new equilibrium expression states shown in (D), while the other two map to equilibrium expression states that are already part of the multifunction. This circuit therefore has f = 3 latent phenotypes, and each is a fixed-point. Other circuits with this bifunction may have more or fewer latent phenotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4061115&req=5

Figure 1: Schematic illustration of a Boolean circuit.(A) Each circuit has N=3 genes, shown as labeled open circles (a,b,c). Genes can be in one of two states: expressed (1) or not expressed (0). Regulatory interactions are depicted as directed edges a→b, which indicate that the gene product of a regulates the expression of b. The signal-integration logic of each gene is captured in a lookup table, where each entry encodes the gene’s regulatory response to one of the 2N possible combinations of the states of its regulating gene products. These lookup tables also specify the circuit’s wiring diagram. For example, the expression of gene a is independent of gene c because its lookup table specifies the Boolean logic function “a and b.” The regulatory interaction c→a is thus inactive, as indicated by the gray color of this edge. (B) By concatenating the rightmost columns of each lookup table, the signal-integration logic and wiring diagram of a circuit can be represented as a single vector G of length L = N × 2N. We consider G to be the circuit’s genotype. (C) The circuit shown in panel (A) is a member of the genotype set of the bifunction F(1):〈0,0,0〉↦〈0,0,0〉, F(2):〈0,0,1〉↦〈0,1,0〉. (D) Each circuit with a given multifunction may map initial states that are not part of the multifunction to new equilibrium states. We consider these to be latent phenotypes. For example, of the five states that are not part of the multifunction shown in (C), three map to the new equilibrium expression states shown in (D), while the other two map to equilibrium expression states that are already part of the multifunction. This circuit therefore has f = 3 latent phenotypes, and each is a fixed-point. Other circuits with this bifunction may have more or fewer latent phenotypes.

Mentions: The model circuits we consider have N = 3 genes (Figure 1A) and are encoded by a genotype that specifies both the topology or “wiring” of the circuit and each gene’s signal-integration logic, i.e., how the gene’s regulatory region integrates signals from other genes to determine the gene’s expression state. We represent this genotype with a binary genotype vector G of length L = N × 2N (Figure 1B). One can think of changes in G as mutations in the cis-regulatory regions that determine a circuit’s topology and signal-integration logic [23,36]. They include mutations that alter the affinity of a transcription factor binding site, its distance from the transcription start site or from another transcription factor binding site, as well as mutations that result in the gain or loss of a regulatory interaction [37]. Such mutations may lead to changes in a circuit’s interpretation of the regulatory state of the cell, thus altering the circuit’s gene expression pattern [38-43].


Latent phenotypes pervade gene regulatory circuits.

Payne JL, Wagner A - BMC Syst Biol (2014)

Schematic illustration of a Boolean circuit.(A) Each circuit has N=3 genes, shown as labeled open circles (a,b,c). Genes can be in one of two states: expressed (1) or not expressed (0). Regulatory interactions are depicted as directed edges a→b, which indicate that the gene product of a regulates the expression of b. The signal-integration logic of each gene is captured in a lookup table, where each entry encodes the gene’s regulatory response to one of the 2N possible combinations of the states of its regulating gene products. These lookup tables also specify the circuit’s wiring diagram. For example, the expression of gene a is independent of gene c because its lookup table specifies the Boolean logic function “a and b.” The regulatory interaction c→a is thus inactive, as indicated by the gray color of this edge. (B) By concatenating the rightmost columns of each lookup table, the signal-integration logic and wiring diagram of a circuit can be represented as a single vector G of length L = N × 2N. We consider G to be the circuit’s genotype. (C) The circuit shown in panel (A) is a member of the genotype set of the bifunction F(1):〈0,0,0〉↦〈0,0,0〉, F(2):〈0,0,1〉↦〈0,1,0〉. (D) Each circuit with a given multifunction may map initial states that are not part of the multifunction to new equilibrium states. We consider these to be latent phenotypes. For example, of the five states that are not part of the multifunction shown in (C), three map to the new equilibrium expression states shown in (D), while the other two map to equilibrium expression states that are already part of the multifunction. This circuit therefore has f = 3 latent phenotypes, and each is a fixed-point. Other circuits with this bifunction may have more or fewer latent phenotypes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061115&req=5

Figure 1: Schematic illustration of a Boolean circuit.(A) Each circuit has N=3 genes, shown as labeled open circles (a,b,c). Genes can be in one of two states: expressed (1) or not expressed (0). Regulatory interactions are depicted as directed edges a→b, which indicate that the gene product of a regulates the expression of b. The signal-integration logic of each gene is captured in a lookup table, where each entry encodes the gene’s regulatory response to one of the 2N possible combinations of the states of its regulating gene products. These lookup tables also specify the circuit’s wiring diagram. For example, the expression of gene a is independent of gene c because its lookup table specifies the Boolean logic function “a and b.” The regulatory interaction c→a is thus inactive, as indicated by the gray color of this edge. (B) By concatenating the rightmost columns of each lookup table, the signal-integration logic and wiring diagram of a circuit can be represented as a single vector G of length L = N × 2N. We consider G to be the circuit’s genotype. (C) The circuit shown in panel (A) is a member of the genotype set of the bifunction F(1):〈0,0,0〉↦〈0,0,0〉, F(2):〈0,0,1〉↦〈0,1,0〉. (D) Each circuit with a given multifunction may map initial states that are not part of the multifunction to new equilibrium states. We consider these to be latent phenotypes. For example, of the five states that are not part of the multifunction shown in (C), three map to the new equilibrium expression states shown in (D), while the other two map to equilibrium expression states that are already part of the multifunction. This circuit therefore has f = 3 latent phenotypes, and each is a fixed-point. Other circuits with this bifunction may have more or fewer latent phenotypes.
Mentions: The model circuits we consider have N = 3 genes (Figure 1A) and are encoded by a genotype that specifies both the topology or “wiring” of the circuit and each gene’s signal-integration logic, i.e., how the gene’s regulatory region integrates signals from other genes to determine the gene’s expression state. We represent this genotype with a binary genotype vector G of length L = N × 2N (Figure 1B). One can think of changes in G as mutations in the cis-regulatory regions that determine a circuit’s topology and signal-integration logic [23,36]. They include mutations that alter the affinity of a transcription factor binding site, its distance from the transcription start site or from another transcription factor binding site, as well as mutations that result in the gain or loss of a regulatory interaction [37]. Such mutations may lead to changes in a circuit’s interpretation of the regulatory state of the cell, thus altering the circuit’s gene expression pattern [38-43].

Bottom Line: Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit's main functions.Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes.Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Zurich, Zurich, Switzerland. andreas.wagner@ieu.uzh.ch.

ABSTRACT

Background: Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations.

Results: Here, we study a space of more than sixteen million three-gene model regulatory circuits, where each circuit is represented by a genotype, and has one or more functions embodied in one or more gene expression phenotypes. We find that the majority of circuits with single functions have latent expression phenotypes. Moreover, the set of circuits with a given spectrum of functions has a repertoire of latent phenotypes that is much larger than that of any one circuit. Most of this latent repertoire can be easily accessed through a series of small genetic changes that preserve a circuit's main functions. Both circuits and gene expression phenotypes that are robust to genetic change are associated with a greater number of latent phenotypes.

Conclusions: Our observations suggest that latent phenotypes are pervasive in regulatory circuits, and may thus be an important source of evolutionary adaptations and innovations involving gene regulation.

Show MeSH