Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks.
Bottom Line: The gene regulatory network (GRN) is the central decision-making module of the cell.BQS explains many of the small- and large-scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response.BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation.
Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom firstname.lastname@example.org.Show MeSH
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Mentions: On studying feedback loops in the GRNs of these organisms (Figure 2A–C, Figure 2—figure supplement 1A,B, lightly shaded bars), we find that P. aeurginosa, S. cerevisiae and human GRNs have no feedback loops comprising three or more genes. The E. coli GRN has no feedback loops comprising four or more genes, and only two 3-gene feedback loops. M. tuberculosis has two 3-gene feedback loops and one 4-gene feedback loop. Notably, all the 3-gene feedback loops observed in real GRNs share the same peculiar structure, with implications discussed below. In contrast, when networks of the size and connectivity of the biological GRNs are constructed with randomly placed links, they display an exponential increase in feedback loops consisting of three or more genes, which number in the thousands (Figure 2A–C, Figure 2—figure supplement 1A,B, heavily shaded bars, and Figure 2—figure supplement 4B). Each of 1000 randomly simulated E. coli networks had at least one long feedback loop. The vastly different abundances of feedback loops clearly demonstrate the profound difference in topologies between real and random networks. Statistical analyses suggest that there is an extremely small probability (<10−6) that the absence of long feedback loops with >3 genes in E. coli is a chance event (Figure 2—figure supplement 2A). Similar results hold for S. cerevisiae (Figure 2—figure supplement 2B) and human (Figure 2—figure supplement 2C). These results are robust to variations in the confidence levels of the E. coli and S. cerevisiae GRNs (Figure 2—figure supplement 3E,J), despite large variations in other properties of the GRNs (Figure 2—figure supplement 3A–D,F–I), and remain valid when different random models are considered (Figure 2—figure supplement 4B).10.7554/eLife.02863.004Figure 2.Feedback loops in real and simulated GRNs.
Affiliation: College of Life Sciences, University of Dundee, Dundee, United Kingdom email@example.com.