Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution

  title={Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution},
  author={Yolanda Schaerli and Alba Jim{\'e}nez and Jos{\'e} M Duarte and Ljiljana Sto{\vs}i{\'c} Mihajlovi{\'c} and Julien Renggli and Mark Isalan and James Sharpe and Andreas Wagner},
  journal={Molecular Systems Biology},
Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits… 

A synthetic synthesis to explore animal evolution and development

It is discussed how techniques borrowed from synthetic biology may facilitate a systematic exploration of evolvability across biological scales and advocate integrating high-throughput experimental data with mathematical and computational techniques from a variety of disciplines in order to pursue a comprehensive theory of evolution.

Environment-dependent epistasis increases phenotypic diversity in gene regulatory networks

A preponderance of epistasis is uncovered in both pairwise and triplet combinations of mutant genotypes that can switch in magnitude and sign across the inducer gradient to produce a greater diversity of expression pattern phenotypes than would be possible in the absence of such environment-dependent epistasis.

Robustness and evolvability in transcriptional regulation

Recent theoretical and experimental work that sheds light on the robustness and evolvability of gene regulatory circuits are reviewed.

Synthetic genotype networks

This work reports the construction of three interconnected genotype networks of synthetic GRNs producing three distinct gene expression phenotypes in Escherichia coli and quantifies robustness and evolvability for the complete genotype-phenotype map and link these features mechanistically to GRN motifs.

Predicting Evolution Using Regulatory Architecture.

These developments are revealing the mechanistic causes of epistasis at different levels of biological organization-in molecular recognition, within a single regulatory network, and between different networks-providing first indications of predictable features of evolutionary constraint.

Gene regulation is commonly selected for high plasticity and low noise

This work quantifies gene expression phenotypes (expression level, plasticity, and noise) for hundreds of promoter variants across multiple environments, and shows that segregating promoter variants are enriched for mutations with minimal effects on expression level.

Gene regulation in Escherichia coli is commonly selected for both high plasticity and low noise.

This work compares differences in the regulatory behaviour of naturally segregating promoter variants from Escherichia coli to randomly mutated promoter variants (which have never been exposed to natural selection), and quantifies gene expression phenotypes (expression level, plasticity and noise) for hundreds of promoter variants across multiple environments.

Addressing evolutionary questions with synthetic biology

This work reviews recent work that implemented synthetic systems, ranging from simple regulatory circuits, rewired cellular networks to artificial genomes and viruses, to study fundamental evolutionary concepts.

Elucidating multi-input processing 3-node gene regulatory network topologies capable of generating striped gene expression patterns

An in silico approach is used to probe the design space of multi-input, three-node Gene Regulatory Networks (GRNs) capable of generating a striped gene expression pattern in the context of a simplified 1-D morphogenetic field.



Dynamics of gene circuits shapes evolvability

It is shown that it is not only the phenotype that determines this evolvability, but also the dynamics of how that phenotype is built during development, which limits the range of possible novel phenotypes accessible by mutation.

Emerging principles of regulatory evolution

Three key operating principles underlying regulatory evolution are identified, that is, how regulatory evolution uses available genetic components in the form of preexisting and active transcription factors and CREs to generate novelty, minimizes the penalty to overall fitness by introducing discrete changes in gene expression and allows interactions to arise among any transcription factor and downstream CRE.

Phenotypic heterogeneity promotes adaptive evolution

This work demonstrates that phenotypic heterogeneity is an evolving trait when populations face a chronic selection pressure and shapes evolutionary trajectories at the genomic level and facilitates evolutionary rescue from a deteriorating environmental stress.

Intersecting transcription networks constrain gene regulatory evolution

The results show that analysing and predicting the evolution of cis-regulatory regions requires an understanding of their positions in overlapping networks, as this placement constrains the available evolutionary pathways.

Innovation and robustness in complex regulatory gene networks

It is concluded that long-term innovation in gene expression patterns can only emerge in the presence of the robustness caused by connected genotype graphs.

Genotype networks shed light on evolutionary constraints.

  • A. Wagner
  • Biology
    Trends in ecology & evolution
  • 2011

Evolving phenotypic networks in silico.

  • P. François
  • Biology
    Seminars in cell & developmental biology
  • 2014

Environmental Dependence of Genetic Constraint

This work systematically reconstructed mutational trajectories from wild type LacI to three different variants that each exhibit an inverse response to the inducing ligand IPTG, and analyzed the higher-order interactions between genetic and environmental changes.

Regulatory network structure determines patterns of intermolecular epistasis

It is found that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site.

Developmental constraints versus flexibility in morphological evolution

It is shown that despite the developmental coupling between different eyespots in the butterfly Bicyclus anynana, there is great potential for independent changes, which is consistent with the diversity of wing patterns across species and argues for a dominant role of natural selection, rather than internal constraints, in shaping existing variation.