Mechanisms of developmental robustness
Introduction
Biological organisms exhibit robustness in the face of environmental perturbations and potential lesions such as mutations. Throughout evolution, there has been a constant selection for inherited mechanisms that are able to keep a trait constant and reproduce stereotyped phenotypic outcomes. Genetic buffering is a term coined to describe these mechanisms. In the literature robustness and canalization are effectively used as synonyms of genetic buffering, however evolutionary nomenclature distinguishes these terms and understands under canalization genetic buffering that has evolved under natural selection in order to stabilize the phenotype and decreases its variability. Canalization allows the accumulation of ‘cryptic genetic variation’ caused by mutations that do not affect the phenotype. Canalized traits are phenotypically expressed only in particular environments or genetic backgrounds and become available for natural selection, a mechanism that can lead to the assimilation of novel traits.
The idea of canalization is first introduced in the 1940s, by the developmental biologist and geneticist C.H. Waddington. He noted that as opposed to mutants, wild type organisms are able to suppress phenotypic variation caused by genetic and environmental changes. In order to explain this fact C.H. Waddington hypothesized that in organism under natural selection the developmental processes are canalized: since cells make discrete fate decisions there must only be a finite number of distinct developmental trajectories possible and each such trajectory, called a chreod, must be stable against small perturbations (Waddington, 1962, Waddington, 1940, Waddington, 1957).
A metaphorical representation of canalization, the C.H. Waddington epigenetic landscape, represents a developing system as a mountainous landscape down which a ball rolls. The ball represents a cell and the selection of developmental pathway happens at each valley branchpoint by the action of embryonic inducing factors or genes. Each landscape valley corresponds to a collection of similar developmental trajectories. If to give the ball a little push toward the hill slope, it will return to the same valley as before, but will end up in another point than before the push. This analogy allows us to understand what canalization means: up to a certain threshold, any genetic variation or environmental noise will be ‘buffered’ and not affect development, but above this threshold, the cell would flip over into another developmental pathway. Contrary to homeostasis, which denotes the stability of the developmental system state, Waddington coined homeoresis as a term to describe the robustness of developmental pathways (Waddington, 1957).
Canalization is thought to be mediated by the buffering activity of specific genes; however, with the one notable exception of hsp90, there have been no facts successfully explaining the molecular mechanisms of canalization as a result of one gene action. On the contrary, new data point that canalization emerges at the level of gene regulatory networks (Wagner, 1996, Bergman and Siegal, 2003, Siegal and Bergman, 2002). For example, a biological system can be robust if the underlying genetic network has redundant interactions – where one interaction can compensate for the loss of another – and/or if the system has distributed robustness – when mutations in one pathway can be compensated by other processes in the system (Wagner, 2005). It is evident that if robustness is indeed an emergent property of a genetic network, we would expect it to break down in mutants affecting factors other than Hsp90. Each mutation in a system—and in particular those affecting regulatory factors—can potentially reduce redundancy and distributed robustness, and render the system more vulnerable to further perturbations. Indeed, Levy and Siegal (2008) identified over 300 mutants in yeast, which exhibit reduced robustness to environmental fluctuations, and Bergman and Siegal (2003) observed widespread loss of canalization when they simulated large numbers of single (one-step) mutants of evolved robust gene regulatory networks.
Thus, the mechanism of canalization and biological robustness remains controversial. However, this problem is at the heart of biology research over the past decade, and the number of publications on this topic is growing rapidly. Here, we summarize the current state of knowledge about several genetic buffering mechanisms.
Section snippets
Mechanisms underlying canalization by molecular chaperone Hsp90
An important implication of the canalization concept is that the buffering mechanism could be genetically controlled. Studies on Hsp90, a molecular chaperone involved in several cellular processes and development pathways, indicate that it is a possible molecular mechanism for canalization and genetic assimilation.
Hsp90 is unusual among chaperones due to the diverse but selective nature of its substrates, most of which are key regulators of growth and development. Hsp90 itself is one of the
Noise buffering by miRNA: the role of feed-forward loops
One of the regulatory mechanisms of gene expression extensively studied in the last years involves microRNA (miRNA) (Bushati and Cohen, 2007, Bartel, 2009). These are small regulatory molecules which bind a recognition sequence of the target protein-coding mRNAs and preclude them from translation. Attached to mRNA molecules, miRNAs can make them either unable for translation or destabilize them, thus decreasing the translation rate or increasing the degradation rate, respectively (
Noise buffering as an emergent property of networks: variance reduction by cross-regulation of gap genes in Drosophila
The above examples show that the noise-reduction mechanism associated with miRNA action essentially can be elucidated by analyzing functions of corresponding FFLs. As FFLs present rather simple motifs, their functions can be understood intuitively. The noise reduction mechanism can also exist as a function of more complex (highly wired) networks, although it may be less intuitive due to the network complexity. A relevant example of this case is the Drosophila gap gene network (Jaeger, 2011).
The
Hidden mechanisms: dynamical role of cell divisions
As the state of a multicellular system is dictated by the state of each cell, the full state space for such system may have extremely great dimensions. Development of the system can be represented as a trajectory inside this space going from an initial to a final state (attractor). When the total number of attractors is large, the correct choice of an appropriate one becomes an important issue. Attractors can be numerous, for example, when the coupling between cells (cell-to-cell communication
Conclusions
We presented a brief overview of recent experimental and theoretical results showing how noise buffering happens in development. This review is far from being complete, as we concentrated only on main issues, which currently are under extensive discussion and on our own input in this field.
The mechanisms described in the paper can be related to the developmental canalization, taking into account various interpretations of this term (Hornstein and Shomron, 2006). The Hsp90 and miRNA functions
Acknowledgments
The study was supported by RFBR grants 10-01-00627a, 11-01-00573a, and 11-04-01162a and the State contract N 14.740.11.0166 from the Russian Ministry of Education and Science.
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