Environment-dependent epistasis increases phenotypic diversity in gene regulatory networks

Abstract

Mutations to gene regulatory networks can be maladaptive or a source of evolutionary novelty. Epistasis confounds our understanding of how mutations impact the expression patterns of gene regulatory networks, because such nonlinearities make it difficult to predict the combined phenotypic effects of mutations based on knowledge of the mutations' individual effects. This challenge is exacerbated by the dependence of epistasis on the environment, which is particularly germane to gene regulatory networks that interpret signals in space or time. To help fill this knowledge gap, we used the toolkit of synthetic biology to systematically assay the effects of pairwise and triplet combinations of mutant genotypes on the expression pattern of a gene regulatory network expressed in Escherichia coli that interprets an inducer gradient across a spatial domain. We uncovered a preponderance of epistasis in both pairwise and triplet combinations 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. We discuss our findings in the context of the evolution of hybrid incompatibilities and evolutionary novelties, arguing that environment-dependent epistasis is likely an important cause of both phenomena in gene regulatory networks.

Improving Genetic Association Studies with a Novel Methodology that Unveils the Hidden Complexity of All-Cause Heart Failure

“…The possibility that epistasis contributes to AHF is further supported by recently discovered epistatic main effect contributions to cardiovascular disease [56]. While we did not discover any heterotic main effects, numerous gene-by-smoking interaction effects showed partial heterosis, hinting that cigarette smoke could influence AHF's epistatic variance, consistent with the observed environmental dependency of bacterial epistatic effects [57]. Future research should explore gene-by-gene-by-environment interactions in heterotic GxE hits, which may elucidate the genetic-environmental interplay in AHF.…”

Mechanistic causes of sign epistasis and its applications

“…In this review, we have delved into sign epistasis from a quantitative genetics perspective, offering a mechanistic understanding of the seemingly intricate interplay of effectswitching genetic mutations and their impacts across diverse biological systems. Understanding the mechanisms giving rise to sign epistasis, rooted in signalling cascades, peaked fitness landscapes, and physical Interactions (Table 1), contributes to advancing genotype-phenotype predictions and developing strategies to address challenges in agriculture (Blanc et al, 2006), antibiotic resistance (Wong, 2017), protein design (Miton and Tokuriki, 2016), and design of sophisticated genetic circuits (Baier et al, 2023).…”

“…Frontiers in Genetics frontiersin.org increasing inducer concentration, over 50% of the significant epistatic pairs exhibit sign epistasis when two mutations are introduced into two of the three components. Notably, when two mutations enhancing output gene expression combine (as depicted in Figure 1B), the majority of significant epistatic pairs manifest as negative reciprocal sign epistasis pairs (Baier et al, 2023). This observation suggests that combinations of beneficial mutations in two genes can frequently result in detrimental effects in such gene regulatory networks.…”

Global regulators facilitate adaptation to a phenotypic trade-off

“…This is significant because growth and swimming are in a trade-off, and selective pressures may favour one or the other. Additionally, our analysis of evolutionary scenarios show that global regulators may not act alone: they must interplay with local regulators, which are required in early evolutionary steps to improve the swimming phenotype [28].…”