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The logic of genetic discovery has changed little over time, but the focus of biology is shifting from simple genotype-phenotype relationships to complex metabolic, physiological, developmental, and behavioral traits. In light of this, the traditional reductionist view of individual genes as privileged difference-making causes of phenotypes is re-examined. The scope and nature of genetic effects in complex regulatory systems, in which dynamics are driven by regulatory feedback and hierarchical interactions across levels of organization are considered. This review argues that it is appropriate to treat genes as specific actual difference-makers for the molecular regulation of gene expression. However, they are often neither stable, proportional, nor specific as causes of the overall dynamic behavior of regulatory networks. Dynamical models, properly formulated and validated, provide the tools to probe cause-and-effect relationships in complex biological systems, allowing to go beyond the limitations of genetic reductionism to gain an integrative understanding of the causal processes underlying complex phenotypes., (© 2020 The Authors. BioEssays published by Wiley Periodicals, Inc.)

The existence of discrete phenotypic traits suggests that the complex regulatory processes which produce them are functionally modular. These processes are usually represented by networks. Only modular networks can be partitioned into intelligible subcircuits able to evolve relatively independently. Traditionally, functional modularity is approximated by detection of modularity in network structure. However, the correlation between structure and function is loose. Many regulatory networks exhibit modular behaviour without structural modularity. Here we partition an experimentally tractable regulatory network-the gap gene system of dipteran insects-using an alternative approach. We show that this system, although not structurally modular, is composed of dynamical modules driving different aspects of whole-network behaviour. All these subcircuits share the same regulatory structure, but differ in components and sensitivity to regulatory interactions. Some subcircuits are in a state of criticality, while others are not, which explains the observed differential evolvability of the various expression features in the system., Competing Interests: BV, NM, JJ No competing interests declared, (© 2019, Verd et al.)

The segmentation gene network in insects can produce equivalent phenotypic outputs despite differences in upstream regulatory inputs between species. We investigate the mechanistic basis of this phenomenon through a systems-level analysis of the gap gene network in the scuttle fly Megaselia abdita (Phoridae). It combines quantification of gene expression at high spatio-temporal resolution with systematic knock-downs by RNA interference (RNAi). Initiation and dynamics of gap gene expression differ markedly between M. abdita and Drosophila melanogaster, while the output of the system converges to equivalent patterns at the end of the blastoderm stage. Although the qualitative structure of the gap gene network is conserved, there are differences in the strength of regulatory interactions between species. We term such network rewiring 'quantitative system drift'. It provides a mechanistic explanation for the developmental hourglass model in the dipteran lineage. Quantitative system drift is likely to be a widespread mechanism for developmental evolution.

Understanding the developmental and evolutionary dynamics of regulatory networks is essential if we are to explain the non-random distribution of phenotypes among the diversity of organismic forms. Here, we present a comparative analysis of one of the best understood developmental gene regulatory networks today: the gap gene network involved in early patterning of insect embryos. We use gene circuit models, which are fitted to quantitative spatio-temporal gene expression data for the four trunk gap genes hunchback (hb), Krüppel (Kr), giant (gt), and knirps (kni)/knirps-like (knl) in the moth midge Clogmia albipunctata, and compare them to equivalent reverse-engineered circuits from our reference species, the vinegar fly Drosophila melanogaster. In contrast to the single network structure we find for D. melanogaster, our models predict four alternative networks for C. albipunctata. These networks share a core structure, which includes the central regulatory feedback between hb and knl. Other interactions are only partially determined, as they differ between our four network structures. Nevertheless, our models make testable predictions and enable us to gain specific insights into gap gene regulation in C. albipunctata. They suggest a less central role for Kr in C. albipunctata than in D. melanogaster, and show that the mechanisms causing an anterior shift of gap domains over time are largely conserved between the two species, although shift dynamics differ. The set of C. albipunctata gene circuit models presented here will be used as the starting point for data-constrained in silico evolutionary simulations to study patterning transitions in the early development of dipteran species., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to discover whether there are rules or regularities governing development and evolution of complex multi-cellular organisms.

Gap genes are involved in segment determination during the early development of the fruit fly Drosophila melanogaster as well as in other insects. This review attempts to synthesize the current knowledge of the gap gene network through a comprehensive survey of the experimental literature. I focus on genetic and molecular evidence, which provides us with an almost-complete picture of the regulatory interactions responsible for trunk gap gene expression. I discuss the regulatory mechanisms involved, and highlight the remaining ambiguities and gaps in the evidence. This is followed by a brief discussion of molecular regulatory mechanisms for transcriptional regulation, as well as precision and size-regulation provided by the system. Finally, I discuss evidence on the evolution of gap gene expression from species other than Drosophila. My survey concludes that studies of the gap gene system continue to reveal interesting and important new insights into the role of gene regulatory networks in development and evolution.

The early embryo of Drosophila melanogaster provides a powerful model system to study the role of genes in pattern formation. The gap gene network constitutes the first zygotic regulatory tier in the hierarchy of the segmentation genes involved in specifying the position of body segments. Here, we use an integrative, systems-level approach to investigate the regulatory effect of the terminal gap gene huckebein (hkb) on gap gene expression. We present quantitative expression data for the Hkb protein, which enable us to include hkb in gap gene circuit models. Gap gene circuits are mathematical models of gene networks used as computational tools to extract regulatory information from spatial expression data. This is achieved by fitting the model to gap gene expression patterns, in order to obtain estimates for regulatory parameters which predict a specific network topology. We show how considering variability in the data combined with analysis of parameter determinability significantly improves the biological relevance and consistency of the approach. Our models are in agreement with earlier results, which they extend in two important respects: First, we show that Hkb is involved in the regulation of the posterior hunchback (hb) domain, but does not have any other essential function. Specifically, Hkb is required for the anterior shift in the posterior border of this domain, which is now reproduced correctly in our models. Second, gap gene circuits presented here are able to reproduce mutants of terminal gap genes, while previously published models were unable to reproduce any null mutants correctly. As a consequence, our models now capture the expression dynamics of all posterior gap genes and some variational properties of the system correctly. This is an important step towards a better, quantitative understanding of the developmental and evolutionary dynamics of the gap gene network.

Background: Mathematical modeling of real-life processes often requires the estimation of unknown parameters. Once the parameters are found by means of optimization, it is important to assess the quality of the parameter estimates, especially if parameter values are used to draw biological conclusions from the model., Results: In this paper we describe how the quality of parameter estimates can be analyzed. We apply our methodology to assess parameter determinability for gene circuit models of the gap gene network in early Drosophila embryos., Conclusion: Our analysis shows that none of the parameters of the considered model can be determined individually with reasonable accuracy due to correlations between parameters. Therefore, the model cannot be used as a tool to infer quantitative regulatory weights. On the other hand, our results show that it is still possible to draw reliable qualitative conclusions on the regulatory topology of the gene network. Moreover, it improves previous analyses of the same model by allowing us to identify those interactions for which qualitative conclusions are reliable, and those for which they are ambiguous.

Axis specification and segment determination in dipteran insects are an excellent model system for comparative analyses of gene network evolution. Antero-posterior polarity of the embryo is established through systems of maternal morphogen gradients. In Drosophila melanogaster, the anterior system acts through opposing gradients of Bicoid (Bcd) and Caudal (Cad), while the posterior system involves Nanos (Nos) and Hunchback (Hb) protein. These systems act redundantly. Both Bcd and Hb need to be eliminated to cause a complete loss of polarity resulting in mirror-duplicated abdomens, so-called bicaudal phenotypes. In contrast, knock-down of bcd alone is sufficient to induce double abdomens in non-drosophilid cyclorrhaphan dipterans such as the hoverfly Episyrphus balteatus or the scuttle fly Megaselia abdita. We investigate conserved and divergent aspects of axis specification in the cyclorrhaphan lineage through a detailed study of the establishment and regulatory effect of maternal gradients in M. abdita. Our results show that the function of the anterior maternal system is highly conserved in this species, despite the loss of maternal cad expression. In contrast, hb does not activate gap genes in this species. The absence of this activatory role provides a precise genetic explanation for the loss of polarity upon bcd knock-down in M. abdita, and suggests a general scenario in which the posterior maternal system is increasingly replaced by the anterior one during the evolution of the cyclorrhaphan dipteran lineage. [ABSTRACT FROM AUTHOR]