Evolutionary and Topological Properties of Genes and Community Structures in Human Gene Regulatory Networks

This work studies the effects of the two rounds of Whole Genome Duplication (WGD) at the origin of the vertebrate lineage on the architecture of the human gene regulatory networks. We integrate information on transcriptional regulation, miRNA regulation, and protein-protein interactions to comparatively analyse the role of WGD and Small Scale Duplications (SSD) in the structural properties of the resulting multilayer network. We show that complex network motifs, such as combinations of feed-forward loops and bifan arrays, deriving from WGD events are specifically enriched in the network. Pairs of WGD-derived proteins display a strong tendency to interact both with each other and with common partners and WGD-derived transcription factors play a prominent role in the retention of a strong regulatory redundancy. Combinatorial regulation and synergy between different regulatory layers are in general enhanced by duplication events, but the two types of duplications contribute in different ways. Overall, our findings suggest that the two WGD events played a substantial role in increasing the multi-layer complexity of the vertebrate regulatory network by enhancing its combinatorial organization, with potential consequences on its overall robustness and ability to perform high-level functions like signal integration and noise control. Lastly, we discuss in detail the RAR/RXR pathway as an illustrative example of the evolutionary impact of WGD duplications in human.

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The impact of whole genome duplications on the human gene regulatory networks

10.1101/2021.07.16.452729 ◽

2021 ◽

Author(s):

Francesco Mottes ◽

Chiara Villa ◽

Matteo Osella ◽

Michele Caselle

Keyword(s):

Gene Regulatory Networks ◽

Protein Interactions ◽

Regulatory Networks ◽

Human Gene ◽

Small Scale ◽

Whole Genome ◽

Mirna Regulation ◽

Vertebrate Lineage ◽

Gene Regulatory ◽

The Impact

This work studies the effects of the two rounds of Whole Genome Duplication (WGD) at the origin of the vertebrate lineage on the architecture of the human gene regulatory networks. We integrate information on transcriptional regulation, miRNA regulation, and protein-protein interactions to comparatively analyse the role of WGD and Small Scale Duplications (SSD) in the structural properties of the resulting multilayer network. We show that complex network motifs, such as combinations of feed-forward loops and bifan arrays, deriving from WGD events are specifically enriched in the network. Pairs of WGD-derived proteins display a strong tendency to interact both with each other and with common partners and WGD-derived transcription factors play a prominent role in the retention of a strong regulatory redundancy. Combinatorial regulation and synergy between different regulatory layers are in general enhanced by duplication events, but the two types of duplications contribute in different ways. Overall, our findings suggest that the two WGD events played a substantial role in increasing the multi-layer complexity of the vertebrate regulatory network by enhancing its combinatorial organization, with potential consequences on its overall robustness and ability to perform high-level functions like signal integration and noise control.

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Inference of Genome-Scale Gene Regulatory Networks: Are There Differences in Biological and Clinical Validations?

Machine Learning and Knowledge Extraction ◽

10.3390/make1010008 ◽

2018 ◽

Vol 1 (1) ◽

pp. 138-148

Author(s):

Frank Emmert-Streib ◽

Matthias Dehmer

Keyword(s):

Gene Regulatory Networks ◽

Regulatory Networks ◽

Human Gene ◽

Expression Data ◽

Research Questions ◽

Gene Regulatory ◽

Experimental Validations ◽

Context Specific ◽

Genome Scale ◽

Network Project

Causal networks, e.g., gene regulatory networks (GRNs) inferred from gene expression data, contain a wealth of information but are defying simple, straightforward and low-budget experimental validations. In this paper, we elaborate on this problem and discuss distinctions between biological and clinical validations. As a result, validation differences for GRNs reflect known differences between basic biological and clinical research questions making the validations context specific. Hence, the meaning of biologically and clinically meaningful GRNs can be very different. For a concerted approach to a problem of this size, we suggest the establishment of the HUMAN GENE REGULATORY NETWORK PROJECT which provides the information required for biological and clinical validations alike.

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