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SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, is evolving into different genetic variants by accumulating mutations as it spreads globally. In addition to this diversity of consensus genomes across patients, RNA viruses can also display genetic diversity within individual hosts, and co-existing viral variants may affect disease progression and the success of medical interventions. To systematically examine the intra-patient genetic diversity of SARS-CoV-2, we processed a large cohort of 3939 publicly-available deeply sequenced genomes with specialised bioinformatics software, along with 749 recently sequenced samples from Switzerland. We found that the distribution of diversity across patients and across genomic loci is very unbalanced with a minority of hosts and positions accounting for much of the diversity. For example, the D614G variant in the Spike gene, which is present in the consensus sequences of 67.4% of patients, is also highly diverse within hosts, with 29.7% of the public cohort being affected by this coexistence and exhibiting different variants. We also investigated the impact of several technical and epidemiological parameters on genetic heterogeneity and found that age, which is known to be correlated with poor disease outcomes, is a significant predictor of viral genetic diversity., bioRxiv

Pathogen genomes provide insights into their evolution and epidemic spread. We sequenced 1,439 SARS-CoV-2 genomes from Switzerland, representing 3-7% of all confirmed cases per week. Using these data, we demonstrate that no one lineage became dominant, pointing against evolution towards general lower virulence. On an epidemiological level, we report no evidence of cryptic transmission before the first confirmed case. We find many early viral introductions from Germany, France, and Italy and many recent introductions from Germany and France. Over the summer, we quantify the number of non-traceable infections stemming from introductions, quantify the effective reproductive number, and estimate the degree of undersampling. Our framework can be applied to quantify evolution and epidemiology in other locations or for other pathogens based on genomic data., medRxiv

Oasis2-Suppl-Material.docx: This file contains supplementary material and figures as well. (DOCX 125 kb)

Purpose: It is still largely unknown, if signaling in the heart in response to pressure overload is conserved in patients and mouse models.The aim of this study is to compare signaling in human biopsies withpressure overload induced compensated hypertrophy (CH) and “mild”failure (HF) to the transverse aortic constriction (TAC) mouse-model ofCH and HF. Using transcriptomics and computational tools we received for the fi rst time a highly comparative data-set comprising expression profi les, signaling pathways and microRNAome changes atdiff erent stages after pressure overload in human and mouse.

Summary Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia., Graphical Abstract, Highlights • Endophilin-A is needed for autophagosome formation in mammalian neurons and brain • Absence of endophilin-A upregulates the E3-ubiquitin ligase FBXO32 • FBXO32-endophilin-A interaction maintains neuronal health and protein homeostasis • Endophilin-A KO mice show age-dependent ataxia, motor impairments, and neurodegeneration, Regulation of protein homeostasis and autophagy has become a promising line of research in the neurodegeneration field. Murdoch et al. now find that endophilin-A, a key factor in clathrin-mediated endocytosis, regulates protein homeostasis through the Foxo3a-Fbxo32 network.

Purpose: Many pathways and genes involved in hypertrophy and heart failurehave been described in animal models, but how the transition from compensatoryhypertrophy to heart failure is initiated in humans remains unclear. This study aimsto identify global mechanisms of gene regulation in the human heart in responseto biomechanical stress (pressure overload) by analyzing the transcriptomes and comparing the contribution of methylation, hydroxymethylation and ncRNAs inaortic stenosis patients with two disease conditions: compensatory hypertrophy(normal ejection fraction) and heart failure (reduced ejection fraction).Methods: DNA and RNA were extracted from snap frozen human myocar-dial biopsy samples and RNA-sequencing (RNA-seq), methylated DNAimmunoprecipitation-sequencing (MeDIP-seq), hydroxymethylated DNAimmunoprecipitation-sequencing (hMeDIP-seq) and smallRNA-sequencing(smallRNA-seq) was carried out using deep HiSeq high throughput sequenc-ing. By comparing the patients’ data to control samples without heart disease usingve replicates for each group and experiment, differentially expressed genes, differ-entially methylated regions, hydroxymethylated regions and differentially expressedmicroRNAs were identied.Results: As expected, the transcriptomes show a high degree of deregulation.Transcriptionfactor (TF) network analysis suggests that approximately 20% ofcondition specic differential expression might be a result of TF regulation. Whilethe methylome is slightly changed in both conditions, the hydroxymethylome ismassively changed in heart failure suggesting a regulatory contribution to thefailing hypertrophic phenotype. Furthermore, differential expression of microRNAsis increased in heart failure and network and target analysis suggests that almost allcandidates are involved in the regulation of differentially expressed genes in both,the compensatory hypertrophy group and heart failure group.Conclusion: The data presented here suggest a regulatory contribution of hydrox-ymethylation and the regulation by microRNAs during the transition of humancompensatory hypertrophy to heart failure.