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Exploring the Genotype–Phenotype Map: Regulatory Pathways

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 24369

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Special Issue Editor

Prof. Dr. Klaus Wimmers

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Guest Editor

Competence Area Genetics and Genomics, Research Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
Interests: animal genomics; transcriptome; epigenome; animal health; animal welfare
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Special Issue Information

Dear Colleagues,

This Special Issue addresses studies focussing on the interdependencies between various levels of the genotype–phenotype map. The previous Special Issue, “Exploring the Genotype–Phenotype Map to Explain Complex Traits”, covered articles reporting the effect of variation at the level of genomes (SNP, CNVs), transcriptomes, proteomes, and metabolomes on complex traits in humans and animals. This second call for contributions especially invites research papers and reviews reporting regulatory pathways within and between the various levels of the genotype–phenotypemap as well as the epigenetic mechanism mediating the effect of environmental effects on the recruitment of genetic information shaping the organismal phenotype.

Prof. Dr. Klaus Wimmers
Guest Editor

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Keywords

network analysis
regulatory pathways
quantitative trait
epigenetics
non-coding RNAs
transcriptomics
proteomics
metabolomics
microarray
next generation sequencing

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Published Papers (6 papers)

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Research

27 pages, 3883 KiB

Open AccessArticle

Reorganization of Metabolism during Cardiomyogenesis Implies Time-Specific Signaling Pathway Regulation

by María Julia Barisón, Isabela Tiemy Pereira, Anny Waloski Robert and Bruno Dallagiovanna

Int. J. Mol. Sci. 2021, 22(3), 1330; https://doi.org/10.3390/ijms22031330 - 29 Jan 2021

Cited by 4 | Viewed by 3107

Abstract

Understanding the cell differentiation process involves the characterization of signaling and regulatory pathways. The coordinated action involved in multilevel regulation determines the commitment of stem cells and their differentiation into a specific cell lineage. Cellular metabolism plays a relevant role in modulating the expression of genes, which act as sensors of the extra-and intracellular environment. In this work, we analyzed mRNAs associated with polysomes by focusing on the expression profile of metabolism-related genes during the cardiac differentiation of human embryonic stem cells (hESCs). We compared different time points during cardiac differentiation (pluripotency, embryoid body aggregation, cardiac mesoderm, cardiac progenitor and cardiomyocyte) and showed the immature cell profile of energy metabolism. Highly regulated canonical pathways are thoroughly discussed, such as those involved in metabolic signaling and lipid homeostasis. We reveal the critical relevance of retinoic X receptor (RXR) heterodimers in upstream retinoic acid metabolism and their relationship with thyroid hormone signaling. Additionally, we highlight the importance of lipid homeostasis and extracellular matrix component biosynthesis during cardiomyogenesis, providing new insights into how hESCs reorganize their metabolism during in vitro cardiac differentiation. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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24 pages, 1813 KiB

Open AccessArticle

Identification and Annotation of Potential Function of Regulatory Antisense Long Non-Coding RNAs Related to Feed Efficiency in Bos taurus Bulls

by Wietje Nolte, Rosemarie Weikard, Ronald M. Brunner, Elke Albrecht, Harald M. Hammon, Antonio Reverter and Christa Kühn

Int. J. Mol. Sci. 2020, 21(9), 3292; https://doi.org/10.3390/ijms21093292 - 6 May 2020

Cited by 9 | Viewed by 3693

Abstract

Long non-coding RNAs (lncRNAs) can influence transcriptional and translational processes in mammalian cells and are associated with various developmental, physiological and phenotypic conditions. However, they remain poorly understood and annotated in livestock species. We combined phenotypic, metabolomics and liver transcriptomic data of bulls divergent for residual feed intake (RFI) and fat accretion. Based on a project-specific transcriptome annotation for the bovine reference genome ARS-UCD.1.2 and multiple-tissue total RNA sequencing data, we predicted 3590 loci to be lncRNAs. To identify lncRNAs with potential regulatory influence on phenotype and gene expression, we applied the regulatory impact factor algorithm on a functionally prioritized set of loci (n = 4666). Applying the algorithm of partial correlation and information theory, significant and independent pairwise correlations were calculated and co-expression networks were established, including plasma metabolites correlated with lncRNAs. The network hub lncRNAs were assessed for potential cis-actions and subjected to biological pathway enrichment analyses. Our results reveal a prevalence of antisense lncRNAs positively correlated with adjacent protein-coding genes and suggest their participation in mitochondrial function, acute phase response signalling, TCA-cycle, fatty acid β-oxidation and presumably gluconeogenesis. These antisense lncRNAs indicate a stabilizing function for their cis-correlated genes and a putative regulatory role in gene expression. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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18 pages, 3959 KiB

Open AccessArticle

Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions

by Siriluck Ponsuksili, Henry Reyer, Frieder Hadlich, Frank Weber, Nares Trakooljul, Michael Oster, Puntita Siengdee, Eduard Muráni, Markus Rodehutscord, Amélia Camarinha-Silva, Jörn Bennewitz and Klaus Wimmers

Int. J. Mol. Sci. 2020, 21(8), 2818; https://doi.org/10.3390/ijms21082818 - 17 Apr 2020

Cited by 15 | Viewed by 4300

Abstract

Phosphorus is an essential mineral for all living organisms and a limited resource worldwide. Variation and heritability of phosphorus utilization (PU) traits were observed, indicating the general possibility of improvement. Molecular mechanisms of PU, including host and microbial effects, are still poorly understood. The most promising molecules that interact between the microbiome and host are microRNAs. Japanese quail representing extremes for PU were selected from an F2 population for miRNA profiling of the ileal tissue and subsequent association with mRNA and microbial data of the same animals. Sixty-nine differentially expressed miRNAs were found, including 21 novel and 48 known miRNAs. Combining miRNAs and mRNAs based on correlated expression and target prediction revealed enrichment of transcripts in functional pathways involved in phosphate or bone metabolism such as RAN, estrogen receptor and Wnt signaling, and immune pathways. Out of 55 genera of microbiota, seven were found to be differentially abundant between PU groups. The study reveals molecular interactions occurring in the gut of quail which represent extremes for PU including miRNA-16-5p, miR-142b-5p, miR-148a-3p, CTDSP1, SMAD3, IGSF10, Bacteroides, and Alistipes as key indicators due to their trait-dependent differential expression and occurrence as hub-members of the network of molecular drivers of PU. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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13 pages, 2608 KiB

Open AccessArticle

Ileal Transcriptome Profiles of Japanese Quail Divergent in Phosphorus Utilization

by Michael Oster, Henry Reyer, Nares Trakooljul, Frank M. Weber, Lu Xi, Eduard Muráni, Siriluck Ponsuksili, Markus Rodehutscord, Jörn Bennewitz and Klaus Wimmers

Int. J. Mol. Sci. 2020, 21(8), 2762; https://doi.org/10.3390/ijms21082762 - 16 Apr 2020

Cited by 7 | Viewed by 3042

Abstract

Phosphorus (P) is an essential component for all living beings. Low P diets prompt phenotypic and molecular adaptations to maintain P homeostasis and increase P utilization (PU). Knowledge of the molecular mechanisms of PU is needed to enable targeted approaches to improve PU efficiency and thus lower P excretion in animal husbandry. In a previous population study, Japanese quail were subjected to a low P diet lacking mineral P and exogenous phytase. Individual PU was determined based on total P intake and excretion. A subset of 20 extreme siblings discordant for PU was selected to retrieve gene expression patterns of ileum (n = 10 per PU group). Sequencing reads have been successfully mapped to the current Coturnix japonica reference genome with an average mapping rate of 86%. In total, 640 genes were found to be differentially abundant between the low and high PU groups (false discovery rate ≤ 0.05). Transcriptional patterns suggest a link between improved PU and mitochondrial energy metabolism, accelerated cell proliferation of enterocytes, and gut integrity. In assessing indicators of the efficient use of macro- and micronutrients, further research on turnover and proliferation rates of intestinal cells could provide an approach to improve P efficiency in poultry species. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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15 pages, 2631 KiB

Open AccessArticle

Genome and Transcriptome Sequencing of casper and roy Zebrafish Mutants Provides Novel Genetic Clues for Iridophore Loss

by Chao Bian, Weiting Chen, Zhiqiang Ruan, Zhe Hu, Yu Huang, Yunyun Lv, Tengfei Xu, Jia Li, Qiong Shi and Wei Ge

Int. J. Mol. Sci. 2020, 21(7), 2385; https://doi.org/10.3390/ijms21072385 - 30 Mar 2020

Cited by 8 | Viewed by 5473

Abstract

casper has been a widely used transparent mutant of zebrafish. It possesses a combined loss of reflective iridophores and light-absorbing melanophores, which gives rise to its almost transparent trunk throughout larval and adult stages. Nevertheless, genomic causal mutations of this transparent phenotype are poorly defined. To identify the potential genetic basis of this fascinating morphological phenotype, we constructed genome maps by performing genome sequencing of 28 zebrafish individuals including wild-type AB strain, roy orbison (roy), and casper mutants. A total of 4.3 million high-quality and high-confidence homozygous single nucleotide polymorphisms (SNPs) were detected in the present study. We also identified a 6.0-Mb linkage disequilibrium block specifically in both roy and casper that was composed of 39 functional genes, of which the mpv17 gene was potentially involved in the regulation of iridophore formation and maintenance. This is the first report of high-confidence genomic mutations in the mpv17 gene of roy and casper that potentially leads to defective splicing as one major molecular clue for the iridophore loss. Additionally, comparative transcriptomic analyses of skin tissues from the AB, roy and casper groups revealed detailed transcriptional changes of several core genes that may be involved in melanophore and iridophore degeneration. In summary, our updated genome and transcriptome sequencing of the casper and roy mutants provides novel genetic clues for the iridophore loss. These new genomic variation maps will offer a solid genetic basis for expanding the zebrafish mutant database and in-depth investigation into pigmentation of animals. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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16 pages, 2247 KiB

Open AccessArticle

Marek’s Disease Virus Infection Induced Mitochondria Changes in Chickens

by Qin Chu, Yi Ding, Wentao Cai, Lei Liu, Huanmin Zhang and Jiuzhou Song

Int. J. Mol. Sci. 2019, 20(13), 3150; https://doi.org/10.3390/ijms20133150 - 27 Jun 2019

Cited by 7 | Viewed by 4089

Abstract

Mitochondria are crucial cellular organelles in eukaryotes and participate in many cell processes including immune response, growth development, and tumorigenesis. Marek’s disease (MD), caused by an avian alpha-herpesvirus Marek’s disease virus (MDV), is characterized with lymphomas and immunosuppression. In this research, we hypothesize that mitochondria may play roles in response to MDV infection. To test it, mitochondrial DNA (mtDNA) abundance and gene expression in immune organs were examined in two well-defined and highly inbred lines of chickens, the MD-susceptible line 7₂ and the MD-resistant line 6₃. We found that mitochondrial DNA contents decreased significantly at the transformation phase in spleen of the MD-susceptible line 7₂ birds in contrast to the MD-resistant line 6₃. The mtDNA-genes and the nucleus-genes relevant to mtDNA maintenance and transcription, however, were significantly up-regulated. Interestingly, we found that POLG2 might play a potential role that led to the imbalance of mtDNA copy number and gene expression alteration. MDV infection induced imbalance of mitochondrial contents and gene expression, demonstrating the indispensability of mitochondria in virus-induced cell transformation and subsequent lymphoma formation, such as MD development in chicken. This is the first report on relationship between virus infection and mitochondria in chicken, which provides important insights into the understanding on pathogenesis and tumorigenesis due to viral infection. Full article

(This article belongs to the Special Issue Exploring the Genotype–Phenotype Map: Regulatory Pathways)

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