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.evolution ͉ gene duplications ͉ modeling ͉ systems biology ͉ noise

Functional analysis of Hsp70 superfamily proteins of rice (Oryza sativa)

“…The transcript of this gene was constitutively high and not affected much by heat stress. On the other hand, it also is the case that functional redundancy has been observed in most gene families in spite of expressional diversification (Kafri et al 2006). In Arabidopsis chloroplast localized two Hsp70 proteins show differential transcript expression.…”

Preferential protection of protein interaction network hubs in yeast: Evolved functionality of genetic redundancy

“…It was suggested that gene duplicates that are consistently coexpressed are unlikely to have redundant functions (4,22). The rationale is that systematically coregulated duplicate genes may be simultaneously required for a given functionality and therefore cannot substitute for each other's absence.…”

“…Taken together, these pieces of evidence suggest that, in particular types of systems, genetic redundancy may play an as-yetunidentified role that could provide a basis for its extended conservation. Although it is unlikely that functional overlaps have been conserved solely for the sake of buffering the mutations (8,19,20), the possibility that they could be advantageously used for a range of different functionalities is intriguing (4,6). If such functionalities do exist, they pose two evolutionary questions.…”

Extending the dynamic range of transcription factor action by translational regulation

“…While finding the optimal input distribution and the corresponding maximal information I is difficult in general, in the case of small noise, σ g ≪ 1, we previously derived a simple formula for the capacity [8]: (36) where (37) (38) and σ c is given either by Eq. (9) for the case of direct transcriptional regulation, or by Eq.…”

“…Several averaging strategies that make transcriptional regulation more reliable have been identified: there is averaging over time as molecules accumulate [2,28,[31][32][33][34], averaging over expression levels of multiple genes that are regulated by the same TF [16,17,38,39], and averaging over space as molecules diffuse between neighboring cells or nuclei, e.g., in a developing embryo [19,[40][41][42][43] or organoid [44]. In the (typical) case where one TF targets multiple genes, there is a regime where information transmission is optimized by complete redundancy in the response of these targets, and another regime in which the concentrations for activation or repression of the targets are staggered so as to "tile" the dynamic range of inputs [16,17].…”