Biology subjects

Fuellen, G.

Publications and source records attributed to Fuellen, G..

4 recordsLinked to original sources

bioRxiv2018

Pathway maps enable straightforward yet customized and semi-automated yet insightful analyses of omics data

To explore the molecular processes underlying some biological theme of interest based on public data, gene lists are used herein as input for the construction of annotated pathway maps, employing Cytoscape apps, and then high-throughput (\"omics\") gene expression data are overlaid onto these maps. Seeded with a published set of marker genes of the senescence-associated secretory phenotype and the genes of the cellular senescence KEGG pathway, a gene/protein interaction network and annotated clusters (a \"pathway map\") of cellular senescence are derived. The map can be amended, by adding some application-specific genes, and overlaid with gene expression data describing cellular senescence of fibroblasts and with disease-related gene expression data associated with prostate and pancreatic cancer, and with ischemic stroke, allowing insights into the role of cellular senescence in disease. Some gene expression data are derived from the \"Biomarker Benchmark repository\". The pathway map approach can be followed in principle for any biological theme of interest, fostering much-needed independence from the investigator-biased expert networks usually used for overlaying gene expression data.

genomics↗

bioRxiv2018

Healthspan pathway maps in C. elegans and humans highlight transcription, prolifera-tion/biosynthesis and lipids

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. However, a precise definition of health and healthspan is not straightforward, and the causal molecular basis of health \"per se\" is largely unknown. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans, featuring the themes transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring the themes immune response, mitochondrion and biosynthesis based on genetic and compound intervention data, and lipids, biosynthesis and transcription based on WormBase compound intervention data. Overlaying healthspan-related gene expression data (describing effects of metabolic intervention associated with improvements in health) onto the aforementioned healthspan pathway maps, we observe the downregulation of Notch signalling in humans and of proliferation/cell-cycle in C. elegans. The former reflects the proinflammatory role of the Notch pathway. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, is available as a reference for future investigations, at http://www.h2020awe.eu/index.php/pathways/.

bioinformatics↗

bioRxiv2017

Combination of mitochondrial tRNA and OXPHOS mutation reduces lifespan and physical condition in aged mice

Mutations in the mitochondrial DNA (mtDNA) are widely known to impact on lifespan and tissue integrity. For example, more than 250 pathogenic mtDNA mutations are known, many of which lead to neurological symptoms. In addition, major neurodegenerative diseases share key components of their etiopathogenesis with regard to mtDNA mutations, mitochondrial dysfunction and oxidative stress. In our study we used a set of conplastic mouse models carrying stable point mutations in mitochondrial genes of transfer RNA (tRNA) and oxidative phosphorylation (OXPHOS)-proteins. We analyzed the impact of these mutations on complex traits like lifespan, learning and memory in the ageing process. The combination of both point mutations in the OXPHOS complex IV gene and adenine insertions in the mitochondrially encoded tRNA arginine (tRNA-Arg) gene (mt-Tr) leads to an age-dependent phenotype with elevated mitochondrial superoxide production in the neocortex. Mice with this combination of tRNA and OXPHOS mutations show significantly reduced lifespan and poor physical constitution at the age of 24 months, whereas single point mutations in OXPHOS or mt-tRNA(Arg) do not have this impact. Therefore, we suggest a synergistic effect of these mutations.

developmental biology↗

bioRxiv2017

Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice

Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e. the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally-arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of a AKR/J mouse strain (B6-mtAKR) together with a C57BL/6J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to wild-type C57BL/6J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair metabolic health and lifespan in mice.\n\nHighlightsO_LIWe identify heteroplasmy of the adenine-repeat variation (9 to 13A) in nt5172 in the origin of light-strand DNA replication (OriL) in inbred mice.\nC_LIO_LIB6-mtAKR mice carry >20% 12A heteroplasmy in the OriL, while B6 mice carry only [~] 10% heteroplasmy.\nC_LIO_LIThe level of 12A heteroplasmy correlates to mtDNA copy number, glucose metabolism, and lifespan in mice.\nC_LIO_LIGiven the established role of mtDNA heteroplasmy in regards to endurance exercise performance in athletes, these findings may impact our understanding of metabolism and aging in humans.\nC_LI

genetics↗