The mechanisms of gene regulatory networks constrain evolution: A lesson from synthetic circuits

Abstract

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 restrictions are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most of the evidence for this is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in E. coli that produce a gene expression stripe - a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

Taming the Beast of Biology: Synthetic Biology and Biological Systems Engineering

“…In the interdisciplinary environment provided by the department's different research pillars -experimental biology, computational biology, and engineering -Synthetic Biology thrives, with major advances in intracellular computation and cellular decision making (groups of Y. Benenson and M. Fussenegger [55] ), genome editing (Platt group [56] ), intracellular control strategies (Khammash group [41] ), computationally supported biodesign (Stelling group [55a] ), immunoengineering (Reddy-group [57] ), and synthetic biochemistry (Panke group [58] ). These efforts are complemented by many other prominent successes in Switzerland, for example in genome synthesis (Christen group [59] ), genetic circuit engineering (Schaerli group [60] ), cellfree engineering (Maerkl group [61] ), biosensors (van der Meer group [62] ), and transfer to industry, as exemplified by the company Evolva (www.evolva.com) and the spin-offs deepCDR Biologics (www.deepcdr.com), FGen (www.fgen.ch), and BioVersys (www. bioversys.com), which hopefully are only the first of a long list of future endeavors.…”