Canalization of Phenotypes—When the Transcriptome is Constantly but Weakly Perturbed

Abstract

Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of GRN (gene regulatory network) stabilization as well as developmental canalization against constant but small environmental perturbations. To analyze mild perturbations, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs by, on average, ∼ 20%. The defining characteristic of stabilizers is that, when their capacity is compromised, GRNs do not change their short-term behaviors. Indeed, even with such broad reductions across all miRNAs, the changes in the transcriptome are very modest during development in stable environment. By comparison, broad knock-downs of other regulatory genes (esp. transcription factors) by the same method should lead to drastic changes in the GRNs. The consequence of de-stabilization may thus be in long-term development as postulated by the theory of canalization. Flies with modest miRNA reductions may gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by ∼ 90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be a solution to weak but constant environmental perturbations.

MicroRNA-mediated network redundancy is constrained by purifying selection and contributes to expression robustness

“…Accumulated evidence indicates that the subtle repression by miRNAs might cumulatively be effective or play crucial roles by regulating multiple functionally relevant targets [8][9][10] . Solid evidence also supports the notion that subtle repression is vital for the canalization of phenotypes and the entire transcriptome 9,11 . Therefore, the functionality of miRNA targeting should be comprehensively understood, particularly in the context of gene regulatory networks or loops.…”

“…The role of miRNA in ne-tuning or buffering gene expression has been extensively investigated 8,11,17,27,32,44 . However, the evolutionary signi cance of miRNA-composed network motifs in gene regulation remains relatively unexplored 25,26 .…”

“…The shock perturbation experiment was conducted following the protocol outlined by Lu et al 11 . Brie y, ies were reared at 25°C on standard sugar-yeast-agar medium under 12:12 hour light/dark cycles.…”

Rapid adaptation of cellular metabolic rate to the MicroRNA complements of mammals and its relevance to the evolution of endothermy

“… 51 Furthermore, these relative rates of translation appear to have evolved under an energy efficiency constraint, 50 which can be understood in light of the 10- to 100-fold higher thermodynamic cost per gene of translation relative to transcription in eukaryotes. 52 , 53 Assuming conservatively that global microRNA activity reduces the global rate of translation by 25%, 54 , 55 , 56 , 57 , 58 a 10-fold increase in cellular MR , without a corresponding increase in global microRNA activity, would incur a 6% loss of efficiency of cellular MR due to protein overproduction (5.4% of overall rMR ), as well as add to the cost of protein degradation. 59 , 60 While not directly comparable, it is worth noting that losses of fitness of up to 3% were found in yeast when the intrinsic translation noise of individual, constitutive proteins was doubled.…”

Rapid Adaptation of Cellular Metabolic Rate to the MicroRNA Complements of Mammals and its Relevance to the Evolution of Endothermy

“…Furthermore, these relative rates of translation appear to have evolved under an energy efficiency constraint (Schwannhäusser et al, 2011), which can be understood in light of the 10-to 100-fold higher thermodynamic cost per gene of translation relative to transcription in eukaryotes (Wagner, 2005; Lynch and Marinov, 2015). Assuming conservatively that global microRNA activity reduces the global rate of translation by 25% (Krek et al, 2005; Baek et al, 2008; Selbach et al, 2008; Spies et al, 2013; Schmiedel et al, 2015; Lu et al, 2023), a 10-fold increase in cellular MR , without a corresponding increase in global microRNA activity, would incur a 6% loss of efficiency of cellular MR (5.4% of overall resing MR, rMR ) due to protein overproduction, as well as add to the cost of protein degradation (Peth et al, 2013; Snoberger et al, 2017). While not directly comparable, it is worth noting that losses of fitness of up to 3% were found when the intrinsic translation noise of individual, constitutive proteins in yeast was doubled (Schmiedel et al, 2019).…”