The regulatory utilization of genetic redundancy through responsive backup circuits

Abstract

Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes. One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses. Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime. In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods. More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated. By manual inspection of the literature, we have compiled a list of such "responsive backup circuits" in a diverse list of species. Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation. We then apply modeling approaches to explore further their dynamic properties. Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precision. We thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation. In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.

Fig. 1.

Specific (A) and general (B) responsive back up circuitries. (A) The Hxt1/Hxt2 responsive backup circuit. Extracellular glucose concentration is sensed by two membrane receptors on the outer yeast membrane, Rgt2 and Snf3. These receptors, once activated by glucose, initiate a signal cascade that induces the transcription of the Hxt gene family of hexose transporters encoding membrane channels for glucose intake. The flux of incoming glucose generates an increase in intracellular glucose concentration, that, in turn, represses the transcription of Hxt2. (B) Three possibilities for feedback in RBCs. For one duplicate gene to sense and respond to its partners’ intactness, feedback mechanisms must be at play. In this diagram, duplicates are represented as ovals that lie embedded within a reaction pathway illustrated by the consecutive arrows. Lines A, B and C represent the three feedback possibilities, namely, simple negative regulation (A), substrate induction (B), and end-product regulation (C).

Fig. 2.

The regulatory wiring for the two distalless developmental regulators dlx3 and dlx7 as deduced from morpholino antisense translation inhibitions (46).

Fig. 3.

Signal robustness provided by RBCs. Three general responsive backup circuitries are examined as follows: simple repression, modeled by equations a1 and a2 (A); dampened controller, modeled by equations b1 and b2 (B); and cycled feedback modeled by equations c1 and c2 (C). β and α represent the rates of protein synthesis and protein degradation, respectively; K_ij is a constant quantifying the regulatory control i has over j. The RBCs are examined for their efficiency in filtering variations of the regulatory input, v₁, of the controller gene, G₁. For each RBC, a diagram is shown describing the regulatory interactions between the responsive and controlling gene. The plots show the dependency of the controller (solid black), the responder (broken black), and their sum, f₂ = G₁ + G₂, (green) on G₁’s induction level, v₁. Induction level is shown in units of K₁₂, such that an induction level of 1 corresponds to 50% saturation of the K₁₂ promoter element. The purple vertical line in B corresponds to v₁/K₁₂ = 100 to help with the comparisons. For a more rigorous treatment, see Supporting Text and Fig. 8.