Sander Wuyts, Renato Alves, Maria Zimmermann-Kogadeeva, Suguru Nishijima, Sonja Blasche, Marja Driessen, Philipp E Geyer, Rajna Hercog, Ece Kartal, Lisa Maier, Johannes B Müller, Sarela Garcia Santamarina, Thomas Sebastian B Schmidt, Daniel C Sevin, Anja Telzerow, Peter V Treit, Tobias Wenzel, Athanasios Typas, Kiran R Patil, Matthias Mann, Michael Kuhn, Peer Bork
{"title":"Consistency across multi-omics layers in a drug-perturbed gut microbial community.","authors":"Sander Wuyts, Renato Alves, Maria Zimmermann-Kogadeeva, Suguru Nishijima, Sonja Blasche, Marja Driessen, Philipp E Geyer, Rajna Hercog, Ece Kartal, Lisa Maier, Johannes B Müller, Sarela Garcia Santamarina, Thomas Sebastian B Schmidt, Daniel C Sevin, Anja Telzerow, Peter V Treit, Tobias Wenzel, Athanasios Typas, Kiran R Patil, Matthias Mann, Michael Kuhn, Peer Bork","doi":"10.15252/msb.202311525","DOIUrl":"10.15252/msb.202311525","url":null,"abstract":"<p><p>Multi-omics analyses are used in microbiome studies to understand molecular changes in microbial communities exposed to different conditions. However, it is not always clear how much each omics data type contributes to our understanding and whether they are concordant with each other. Here, we map the molecular response of a synthetic community of 32 human gut bacteria to three non-antibiotic drugs by using five omics layers (16S rRNA gene profiling, metagenomics, metatranscriptomics, metaproteomics and metabolomics). We find that all the omics methods with species resolution are highly consistent in estimating relative species abundances. Furthermore, different omics methods complement each other for capturing functional changes. For example, while nearly all the omics data types captured that the antipsychotic drug chlorpromazine selectively inhibits Bacteroidota representatives in the community, the metatranscriptome and metaproteome suggested that the drug induces stress responses related to protein quality control. Metabolomics revealed a decrease in oligosaccharide uptake, likely caused by Bacteroidota depletion. Our study highlights how multi-omics datasets can be utilized to reveal complex molecular responses to external perturbations in microbial communities.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 9","pages":"e11525"},"PeriodicalIF":9.9,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10240795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Javier Ruiz, Miguel de Celis, Juan Diaz-Colunga, Jean Cc Vila, Belen Benitez-Dominguez, Javier Vicente, Antonio Santos, Alvaro Sanchez, Ignacio Belda
{"title":"Predictability of the community-function landscape in wine yeast ecosystems.","authors":"Javier Ruiz, Miguel de Celis, Juan Diaz-Colunga, Jean Cc Vila, Belen Benitez-Dominguez, Javier Vicente, Antonio Santos, Alvaro Sanchez, Ignacio Belda","doi":"10.15252/msb.202311613","DOIUrl":"10.15252/msb.202311613","url":null,"abstract":"<p><p>Predictively linking taxonomic composition and quantitative ecosystem functions is a major aspiration in microbial ecology, which must be resolved if we wish to engineer microbial consortia. Here, we have addressed this open question for an ecological function of major biotechnological relevance: alcoholic fermentation in wine yeast communities. By exhaustively phenotyping an extensive collection of naturally occurring wine yeast strains, we find that most ecologically and industrially relevant traits exhibit phylogenetic signal, allowing functional traits in wine yeast communities to be predicted from taxonomy. Furthermore, we demonstrate that the quantitative contributions of individual wine yeast strains to the function of complex communities followed simple quantitative rules. These regularities can be integrated to quantitatively predict the function of newly assembled consortia. Besides addressing theoretical questions in functional ecology, our results and methodologies can provide a blueprint for rationally managing microbial processes of biotechnological relevance.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 9","pages":"e11613"},"PeriodicalIF":8.5,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10291995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lara Urban, Albert Perlas, Olga Francino, Joan Martí-Carreras, Brenda A Muga, Jenniffer W Mwangi, Laura Boykin Okalebo, Jo-Ann L Stanton, Amanda Black, Nick Waipara, Claudia Fontsere, David Eccles, Harika Urel, Tim Reska, Hernán E Morales, Marc Palmada-Flores, Tomas Marques-Bonet, Mrinalini Watsa, Zane Libke, Gideon Erkenswick, Cock van Oosterhout
{"title":"Real-time genomics for One Health.","authors":"Lara Urban, Albert Perlas, Olga Francino, Joan Martí-Carreras, Brenda A Muga, Jenniffer W Mwangi, Laura Boykin Okalebo, Jo-Ann L Stanton, Amanda Black, Nick Waipara, Claudia Fontsere, David Eccles, Harika Urel, Tim Reska, Hernán E Morales, Marc Palmada-Flores, Tomas Marques-Bonet, Mrinalini Watsa, Zane Libke, Gideon Erkenswick, Cock van Oosterhout","doi":"10.15252/msb.202311686","DOIUrl":"10.15252/msb.202311686","url":null,"abstract":"<p><p>The ongoing degradation of natural systems and other environmental changes has put our society at a crossroad with respect to our future relationship with our planet. While the concept of One Health describes how human health is inextricably linked with environmental health, many of these complex interdependencies are still not well-understood. Here, we describe how the advent of real-time genomic analyses can benefit One Health and how it can enable timely, in-depth ecosystem health assessments. We introduce nanopore sequencing as the only disruptive technology that currently allows for real-time genomic analyses and that is already being used worldwide to improve the accessibility and versatility of genomic sequencing. We showcase real-time genomic studies on zoonotic disease, food security, environmental microbiome, emerging pathogens, and their antimicrobial resistances, and on environmental health itself - from genomic resource creation for wildlife conservation to the monitoring of biodiversity, invasive species, and wildlife trafficking. We stress why equitable access to real-time genomics in the context of One Health will be paramount and discuss related practical, legal, and ethical limitations.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11686"},"PeriodicalIF":8.5,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9963827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eyal Simonovsky, Moran Sharon, Maya Ziv, Omry Mauer, Idan Hekselman, Juman Jubran, Ekaterina Vinogradov, Chanan M Argov, Omer Basha, Lior Kerber, Yuval Yogev, Ayellet V Segrè, Hae Kyung Im, Ohad Birk, Lior Rokach, Esti Yeger-Lotem
{"title":"Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.","authors":"Eyal Simonovsky, Moran Sharon, Maya Ziv, Omry Mauer, Idan Hekselman, Juman Jubran, Ekaterina Vinogradov, Chanan M Argov, Omer Basha, Lior Kerber, Yuval Yogev, Ayellet V Segrè, Hae Kyung Im, Ohad Birk, Lior Rokach, Esti Yeger-Lotem","doi":"10.15252/msb.202211407","DOIUrl":"10.15252/msb.202211407","url":null,"abstract":"<p><p>How do aberrations in widely expressed genes lead to tissue-selective hereditary diseases? Previous attempts to answer this question were limited to testing a few candidate mechanisms. To answer this question at a larger scale, we developed \"Tissue Risk Assessment of Causality by Expression\" (TRACE), a machine learning approach to predict genes that underlie tissue-selective diseases and selectivity-related features. TRACE utilized 4,744 biologically interpretable tissue-specific gene features that were inferred from heterogeneous omics datasets. Application of TRACE to 1,031 disease genes uncovered known and novel selectivity-related features, the most common of which was previously overlooked. Next, we created a catalog of tissue-associated risks for 18,927 protein-coding genes (https://netbio.bgu.ac.il/trace/). As proof-of-concept, we prioritized candidate disease genes identified in 48 rare-disease patients. TRACE ranked the verified disease gene among the patient's candidate genes significantly better than gene prioritization methods that rank by gene constraint or tissue expression. Thus, tissue selectivity combined with machine learning enhances genetic and clinical understanding of hereditary diseases.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11407"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10318151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kyle Mohler, Jack M Moen, Svetlana Rogulina, Jesse Rinehart
{"title":"System-wide optimization of an orthogonal translation system with enhanced biological tolerance.","authors":"Kyle Mohler, Jack M Moen, Svetlana Rogulina, Jesse Rinehart","doi":"10.15252/msb.202110591","DOIUrl":"https://doi.org/10.15252/msb.202110591","url":null,"abstract":"<p><p>Over the past two decades, synthetic biological systems have revolutionized the study of cellular physiology. The ability to site-specifically incorporate biologically relevant non-standard amino acids using orthogonal translation systems (OTSs) has proven particularly useful, providing unparalleled access to cellular mechanisms modulated by post-translational modifications, such as protein phosphorylation. However, despite significant advances in OTS design and function, the systems-level biology of OTS development and utilization remains underexplored. In this study, we employ a phosphoserine OTS (pSerOTS) as a model to systematically investigate global interactions between OTS components and the cellular environment, aiming to improve OTS performance. Based on this analysis, we design OTS variants to enhance orthogonality by minimizing host process interactions and reducing stress response activation. Our findings advance understanding of system-wide OTS:host interactions, enabling informed design practices that circumvent deleterious interactions with host physiology while improving OTS performance and stability. Furthermore, our study emphasizes the importance of establishing a pipeline for systematically profiling OTS:host interactions to enhance orthogonality and mitigate mechanisms underlying OTS-mediated host toxicity.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e10591"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9964398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthias Weith, Jan Großbach, Mathieu Clement-Ziza, Ludovic Gillet, María Rodríguez-López, Samuel Marguerat, Christopher T Workman, Paola Picotti, Jürg Bähler, Ruedi Aebersold, Andreas Beyer
{"title":"Genetic effects on molecular network states explain complex traits.","authors":"Matthias Weith, Jan Großbach, Mathieu Clement-Ziza, Ludovic Gillet, María Rodríguez-López, Samuel Marguerat, Christopher T Workman, Paola Picotti, Jürg Bähler, Ruedi Aebersold, Andreas Beyer","doi":"10.15252/msb.202211493","DOIUrl":"https://doi.org/10.15252/msb.202211493","url":null,"abstract":"<p><p>The complexity of many cellular and organismal traits results from the integration of genetic and environmental factors via molecular networks. Network structure and effect propagation are best understood at the level of functional modules, but so far, no concept has been established to include the global network state. Here, we show when and how genetic perturbations lead to molecular changes that are confined to small parts of a network versus when they lead to modulation of network states. Integrating multi-omics profiling of genetically heterogeneous budding and fission yeast strains with an array of cellular traits identified a central state transition of the yeast molecular network that is related to PKA and TOR (PT) signaling. Genetic variants affecting this PT state globally shifted the molecular network along a single-dimensional axis, thereby modulating processes including energy and amino acid metabolism, transcription, translation, cell cycle control, and cellular stress response. We propose that genetic effects can propagate through large parts of molecular networks because of the functional requirement to centrally coordinate the activity of fundamental cellular processes.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11493"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10318644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Updated benchmarking of variant effect predictors using deep mutational scanning.","authors":"Benjamin J Livesey, Joseph A Marsh","doi":"10.15252/msb.202211474","DOIUrl":"10.15252/msb.202211474","url":null,"abstract":"<p><p>The assessment of variant effect predictor (VEP) performance is fraught with biases introduced by benchmarking against clinical observations. In this study, building on our previous work, we use independently generated measurements of protein function from deep mutational scanning (DMS) experiments for 26 human proteins to benchmark 55 different VEPs, while introducing minimal data circularity. Many top-performing VEPs are unsupervised methods including EVE, DeepSequence and ESM-1v, a protein language model that ranked first overall. However, the strong performance of recent supervised VEPs, in particular VARITY, shows that developers are taking data circularity and bias issues seriously. We also assess the performance of DMS and unsupervised VEPs for discriminating between known pathogenic and putatively benign missense variants. Our findings are mixed, demonstrating that some DMS datasets perform exceptionally at variant classification, while others are poor. Notably, we observe a striking correlation between VEP agreement with DMS data and performance in identifying clinically relevant variants, strongly supporting the validity of our rankings and the utility of DMS for independent benchmarking.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 8","pages":"e11474"},"PeriodicalIF":9.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10407742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9960586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucas van Duin, Robert Krautz, Sarah Rennie, Robin Andersson
{"title":"Transcription factor expression is the main determinant of variability in gene co-activity.","authors":"Lucas van Duin, Robert Krautz, Sarah Rennie, Robin Andersson","doi":"10.15252/msb.202211392","DOIUrl":"10.15252/msb.202211392","url":null,"abstract":"<p><p>Many genes are co-expressed and form genomic domains of coordinated gene activity. However, the regulatory determinants of domain co-activity remain unclear. Here, we leverage human individual variation in gene expression to characterize the co-regulatory processes underlying domain co-activity and systematically quantify their effect sizes. We employ transcriptional decomposition to extract from RNA expression data an expression component related to co-activity revealed by genomic positioning. This strategy reveals close to 1,500 co-activity domains, covering most expressed genes, of which the large majority are invariable across individuals. Focusing specifically on domains with high variability in co-activity reveals that contained genes have a higher sharing of eQTLs, a higher variability in enhancer interactions, and an enrichment of binding by variably expressed transcription factors, compared to genes within non-variable domains. Through careful quantification of the relative contributions of regulatory processes underlying co-activity, we find transcription factor expression levels to be the main determinant of gene co-activity. Our results indicate that distal trans effects contribute more than local genetic variation to individual variation in co-activity domains.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11392"},"PeriodicalIF":8.5,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9789760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Polychronidou, Jingyi Hou, M Madan Babu, Prisca Liberali, Ido Amit, Bart Deplancke, Galit Lahav, Shalev Itzkovitz, Matthias Mann, Julio Saez-Rodriguez, Fabian Theis, Roland Eils
{"title":"Single-cell biology: what does the future hold?","authors":"Maria Polychronidou, Jingyi Hou, M Madan Babu, Prisca Liberali, Ido Amit, Bart Deplancke, Galit Lahav, Shalev Itzkovitz, Matthias Mann, Julio Saez-Rodriguez, Fabian Theis, Roland Eils","doi":"10.15252/msb.202311799","DOIUrl":"https://doi.org/10.15252/msb.202311799","url":null,"abstract":"<p><p>In this Editorial, our Chief Editor and members of our Advisory Editorial Board discuss recent breakthroughs, current challenges, and emerging opportunities in single-cell biology and share their vision of \"where the field is headed.\"</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11799"},"PeriodicalIF":9.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10155980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E Davey, Ylva Ivarsson
{"title":"Large-scale phosphomimetic screening identifies phospho-modulated motif-based protein interactions.","authors":"Johanna Kliche, Dimitriya Hristoforova Garvanska, Leandro Simonetti, Dilip Badgujar, Doreen Dobritzsch, Jakob Nilsson, Norman E Davey, Ylva Ivarsson","doi":"10.15252/msb.202211164","DOIUrl":"10.15252/msb.202211164","url":null,"abstract":"<p><p>Phosphorylation is a ubiquitous post-translation modification that regulates protein function by promoting, inhibiting or modulating protein-protein interactions. Hundreds of thousands of phosphosites have been identified but the vast majority have not been functionally characterised and it remains a challenge to decipher phosphorylation events modulating interactions. We generated a phosphomimetic proteomic peptide-phage display library to screen for phosphosites that modulate short linear motif-based interactions. The peptidome covers ~13,500 phospho-serine/threonine sites found in the intrinsically disordered regions of the human proteome. Each phosphosite is represented as wild-type and phosphomimetic variant. We screened 71 protein domains to identify 248 phosphosites that modulate motif-mediated interactions. Affinity measurements confirmed the phospho-modulation of 14 out of 18 tested interactions. We performed a detailed follow-up on a phospho-dependent interaction between clathrin and the mitotic spindle protein hepatoma-upregulated protein (HURP), demonstrating the essentiality of the phospho-dependency to the mitotic function of HURP. Structural characterisation of the clathrin-HURP complex elucidated the molecular basis for the phospho-dependency. Our work showcases the power of phosphomimetic ProP-PD to discover novel phospho-modulated interactions required for cellular function.</p>","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"19 7","pages":"e11164"},"PeriodicalIF":9.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9794572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}