Multi-Level Integration of Environmentally Perturbed Internal Phenotypes Reveals Key Points of Connectivity between Them

Abstract

The genotype and external phenotype of organisms are linked by so-called internal phenotypes which are influenced by environmental conditions. In this study, we used five existing -omics datasets representing five different layers of internal phenotypes, which were simultaneously measured in dietarily perturbed mice. We performed 10 pair-wise correlation analyses verified with a null model built from randomized data. Subsequently, the inferred networks were merged and literature mined for co-occurrences of identified linked nodes. Densely connected internal phenotypes emerged. Forty-five nodes have links with all other data-types and we denote them “connectivity hubs.” In literature, we found proof of 6% of the 577 connections, suggesting a biological meaning for the observed correlations. The observed connectivities between metabolite and cytokines hubs showed higher numbers of literature hits as compared to the number of literature hits on the connectivities between the microbiota and gene expression internal phenotypes. We conclude that multi-level integrated networks may help to generate hypotheses and to design experiments aiming to further close the gap between genotype and phenotype. We describe and/or hypothesize on the biological relevance of four identified multi-level connectivity hubs.

Dietary supplementation of zinc oxide modulates intestinal functionality during the post-weaning period in clinically healthy piglets

“…Furthermore, the C3 gene is known to have an antimicrobial activity [ 58 ]. In mice it has already been described that genes involved in the complement system respond to different (oral) challenges, i.e., dietary, drug, or immune [ 59 ]. Consequently the complement pathway functioning changes by increased expression of genes C2 , C3 , C4 , CD55 , and factor H, which may be needed as an early defence mechanism against dysbiosis/infection or a dysfunctional barrier [ 59 ].…”

“…In mice it has already been described that genes involved in the complement system respond to different (oral) challenges, i.e., dietary, drug, or immune [ 59 ]. Consequently the complement pathway functioning changes by increased expression of genes C2 , C3 , C4 , CD55 , and factor H, which may be needed as an early defence mechanism against dysbiosis/infection or a dysfunctional barrier [ 59 ]. In addition, the gene encoding for MT1A belongs to the metallothionein gene family, which has a high content of cysteine residues that can bind various heavy metals, including zinc.…”

The Importance of Endophenotypes to Evaluate the Relationship between Genotype and External Phenotype

“…Examples in reference animals such as mice show the possibilities at this stage. Excellent examples are the studies of Orozco et al [ 18 ] and Benis et al [ 162 ], both using mice as sources of experimental data. In a highly interesting study, Orozco et al [ 18 ] showed how the genotype affected some part of the methylome, while other parts were environmentally affected, how the profiles of gene expression were regulated at the RNA and proteome levels and how the metabolome profile reacted.…”

“…In a highly interesting study, Orozco et al [ 18 ] showed how the genotype affected some part of the methylome, while other parts were environmentally affected, how the profiles of gene expression were regulated at the RNA and proteome levels and how the metabolome profile reacted. Benis et al [ 162 ] showed the integration of five biological levels: microbiota, transcriptomics, cytokine and metabolomics in serum and urine, pointing towards several connections between the layers and within the layers. This clearly shows the power of such studies for understanding complex traits by linking the genotype and several phenome levels to the external complex trait phenotype.…”