Transcription control reprogramming in genetic backup circuits

Abstract

A key question in molecular genetics is why severe mutations often do not result in a detectably abnormal phenotype. This robustness was partially ascribed to redundant paralogs that may provide backup for one another in case of mutation. Mining mutant viability and mRNA expression data in Saccharomyces cerevisiae, we found that backup was provided predominantly by paralogs that are expressed dissimilarly in most growth conditions. We considered that this apparent inconsistency might be resolved by a transcriptional reprogramming mechanism that allows the intact paralog to rescue the organism upon mutation of its counterpart. We found that in wild-type cells, partial coregulation across growth conditions predicted the ability of paralogs to alter their transcription patterns and to provide backup for one another. Notably, the sets of regulatory motifs that controlled the paralogs with the most efficient backup activity deliberately overlapped only partially; paralogs with highly similar or dissimilar sets of motifs had suboptimal backup activity. Such an arrangement of partially shared regulatory motifs reconciles the differential expression of paralogs with their ability to back each other up.

Systems biology and the integration of mechanistic explanation and mathematical explanation

“…) In some instances robustness results from redundancy, where two copies of a structure are present so that the loss of one structure does not have any impact (Dean et al, 2008). But even in the case of a duplicated gene, there often have to be functional amendments, as an active mechanism has to turn on the second gene copy which is normally not expressed (Baggs et al, 2009;Kafri et al, 2005). Usually robustness is not just due to structural redundancy, but is a distributed functional process in that the overall system undergoes various functional changes to compensate for the loss of one component (Ihmels et al, 2007;Wagner, 2005aWagner, , 2005b.…”

The regulatory code for transcriptional response diversity and its relation to genome structural properties in Arabidopsis thaliana

“…However, results reported in yeast suggest that rather than redundancy provided by duplicated genes, interactions between unrelated genes appear to be responsible for robustness against mutations [40]. Furthermore, rather than a static robustness provided by ''replacement parts,'' a dynamic reprogramming of the transcriptional regulatory network may be employed during ''fail-safe'' scenarios [41].…”

Uncovering a Hidden Distributed Architecture Behind Scale-free Transcriptional Regulatory Networks

“…gene duplicates (paralogs) and analogous proteins. [12][13][14][15][16][17] However, the role of distributed robustness remains poorly understood. 9 Earlier studies on mutational robustness have concentrated primarily on individual genes, or on a set of genes that act in the same functional pathway.…”

“…9 Earlier studies on mutational robustness have concentrated primarily on individual genes, or on a set of genes that act in the same functional pathway. 9,[18][19][20][21] Even though further studies have addressed the role of redundancy 9,12,22,23 in various molecular interaction networks, including protein regulatory networks, very few studies have investigated the collective properties of real biological networks, which are required to evaluate the significance of concepts like distributed robustness. In this context, the technological advances in high-throughput genomics and proteomics place us in a unique position to reconstruct the interaction network of most genes, and to study them as an integrated system rather than in isolation or as a small group of interacting proteins.…”