Molecular Systems Biology最新文献_第9页

Mapping temperature-sensitive mutations at a genome scale to engineer growth switches in Escherichia coli. 在基因组范围内绘制温度敏感突变图，以设计大肠杆菌的生长开关。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-10-12 Epub Date: 2023-08-29 DOI: 10.15252/msb.202311596

Thorben Schramm, Paul Lubrano, Vanessa Pahl, Amelie Stadelmann, Andreas Verhülsdonk, Hannes Link

{"title":"Mapping temperature-sensitive mutations at a genome scale to engineer growth switches in Escherichia coli.","authors":"Thorben Schramm, Paul Lubrano, Vanessa Pahl, Amelie Stadelmann, Andreas Verhülsdonk, Hannes Link","doi":"10.15252/msb.202311596","DOIUrl":"10.15252/msb.202311596","url":null,"abstract":"Temperature-sensitive (TS) mutants are a unique tool to perturb and engineer cellular systems. Here, we constructed a CRISPR library with 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. 1,269 of these mutants showed temperature-sensitive growth in a time-resolved competition assay. We reconstructed 94 TS mutants and measured their metabolism under growth arrest at 42°C using metabolomics. Metabolome changes were strong and mutant-specific, showing that metabolism of nongrowing E. coli is perturbation-dependent. For example, 24 TS mutants of metabolic enzymes overproduced the direct substrate metabolite due to a bottleneck in their associated pathway. A strain with TS homoserine kinase (ThrBF267D ) produced homoserine for 24 h, and production was tunable by temperature. Finally, we used a TS subunit of DNA polymerase III (DnaXL289Q ) to decouple growth from arginine overproduction in engineered E. coli. These results provide a strategy to identify TS mutants en masse and demonstrate their large potential to produce bacterial metabolites with nongrowing cells.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10112762","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}

引用次数: 1

SLAM-Drop-seq reveals mRNA kinetic rates throughout the cell cycle. SLAM - Drop - seq揭示了整个细胞周期中mRNA的动力学速率

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-10-01 Epub Date: 2023-08-28 DOI: 10.15252/msb.202211427

Haiyue Liu, Roberto Arsiè, Daniel Schwabe, Marcel Schilling, Igor Minia, Jonathan Alles, Anastasiya Boltengagen, Christine Kocks, Martin Falcke, Nir Friedman, Markus Landthaler, Nikolaus Rajewsky

{"title":"SLAM-Drop-seq reveals mRNA kinetic rates throughout the cell cycle.","authors":"Haiyue Liu, Roberto Arsiè, Daniel Schwabe, Marcel Schilling, Igor Minia, Jonathan Alles, Anastasiya Boltengagen, Christine Kocks, Martin Falcke, Nir Friedman, Markus Landthaler, Nikolaus Rajewsky","doi":"10.15252/msb.202211427","DOIUrl":"10.15252/msb.202211427","url":null,"abstract":"RNA abundance is tightly regulated in eukaryotic cells by modulating the kinetic rates of RNA production, processing, and degradation. To date, little is known about time‐dependent kinetic rates during dynamic processes. Here, we present SLAM‐Drop‐seq, a method that combines RNA metabolic labeling and alkylation of modified nucleotides in methanol‐fixed cells with droplet‐based sequencing to detect newly synthesized and preexisting mRNAs in single cells. As a first application, we sequenced 7280 HEK293 cells and calculated gene‐specific kinetic rates during the cell cycle using the novel package Eskrate. Of the 377 robust‐cycling genes that we identified, only a minor fraction is regulated solely by either dynamic transcription or degradation (6 and 4%, respectively). By contrast, the vast majority (89%) exhibit dynamically regulated transcription and degradation rates during the cell cycle. Our study thus shows that temporally regulated mRNA degradation is fundamental for the correct expression of a majority of cycling genes. SLAM‐Drop‐seq, combined with Eskrate, is a powerful approach to understanding the underlying mRNA kinetics of single‐cell gene expression dynamics in continuous biological processes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42650591","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}

引用次数: 0

Robust dimethyl-based multiplex-DIA doubles single-cell proteome depth via a reference channel. 稳健的基于二甲基的多重DIA通过参考通道使单细胞蛋白质组深度加倍。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-09-12 Epub Date: 2023-08-21 DOI: 10.15252/msb.202211503

Marvin Thielert, Ericka Cm Itang, Constantin Ammar, Florian A Rosenberger, Isabell Bludau, Lisa Schweizer, Thierry M Nordmann, Patricia Skowronek, Maria Wahle, Wen-Feng Zeng, Xie-Xuan Zhou, Andreas-David Brunner, Sabrina Richter, Mitchell P Levesque, Fabian J Theis, Martin Steger, Matthias Mann

{"title":"Robust dimethyl-based multiplex-DIA doubles single-cell proteome depth via a reference channel.","authors":"Marvin Thielert, Ericka Cm Itang, Constantin Ammar, Florian A Rosenberger, Isabell Bludau, Lisa Schweizer, Thierry M Nordmann, Patricia Skowronek, Maria Wahle, Wen-Feng Zeng, Xie-Xuan Zhou, Andreas-David Brunner, Sabrina Richter, Mitchell P Levesque, Fabian J Theis, Martin Steger, Matthias Mann","doi":"10.15252/msb.202211503","DOIUrl":"10.15252/msb.202211503","url":null,"abstract":"Single-cell proteomics aims to characterize biological function and heterogeneity at the level of proteins in an unbiased manner. It is currently limited in proteomic depth, throughput, and robustness, which we address here by a streamlined multiplexed workflow using data-independent acquisition (mDIA). We demonstrate automated and complete dimethyl labeling of bulk or single-cell samples, without losing proteomic depth. Lys-N digestion enables five-plex quantification at MS1 and MS2 level. Because the multiplexed channels are quantitatively isolated from each other, mDIA accommodates a reference channel that does not interfere with the target channels. Our algorithm RefQuant takes advantage of this and confidently quantifies twice as many proteins per single cell compared to our previous work (Brunner et al, PMID 35226415), while our workflow currently allows routine analysis of 80 single cells per day. Finally, we combined mDIA with spatial proteomics to increase the throughput of Deep Visual Proteomics seven-fold for microdissection and four-fold for MS analysis. Applying this to primary cutaneous melanoma, we discovered proteomic signatures of cells within distinct tumor microenvironments, showcasing its potential for precision oncology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"PeriodicalIF":8.5,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10236507","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}

引用次数: 0

Consistency across multi-omics layers in a drug-perturbed gut microbial community. 药物干扰肠道微生物群落中多组学层的一致性。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-09-12 Epub Date: 2023-07-24 DOI: 10.15252/msb.202311525

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 1

Predictability of the community-function landscape in wine yeast ecosystems. 葡萄酒酵母生态系统中群落功能景观的可预测性。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-09-12 Epub Date: 2023-08-07 DOI: 10.15252/msb.202311613

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 0

Real-time genomics for One Health. 实时基因组学促进 "一体健康"。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 Epub Date: 2023-06-16 DOI: 10.15252/msb.202311686

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 0

Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation. 利用遗传疾病的组织选择性表现预测遗传疾病的分子机制。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 Epub Date: 2023-05-26 DOI: 10.15252/msb.202211407

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 2

System-wide optimization of an orthogonal translation system with enhanced biological tolerance. 具有增强生物耐受性的正交翻译系统的全系统优化。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 DOI: 10.15252/msb.202110591

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 0

Genetic effects on molecular network states explain complex traits. 遗传对分子网络状态的影响解释了复杂的性状。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 DOI: 10.15252/msb.202211493

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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 1

Updated benchmarking of variant effect predictors using deep mutational scanning. 利用深度突变扫描更新变异效应预测器的基准。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-08-08 Epub Date: 2023-06-13 DOI: 10.15252/msb.202211474

Benjamin J Livesey, Joseph A Marsh

{"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":"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.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":null,"pages":null},"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}

引用次数: 0