The structural coverage of the human proteome before and after AlphaFold DOI Creative Commons
Eduard Porta‐Pardo, Victoria Ruiz‐Serra, Samuel Valentini

et al.

PLoS Computational Biology, Journal Year: 2022, Volume and Issue: 18(1), P. e1009818 - e1009818

Published: Jan. 24, 2022

The protein structure field is experiencing a revolution. From the increased throughput of techniques to determine experimental structures, developments such as cryo-EM that allow us find structures large complexes or, more recently, development artificial intelligence tools, AlphaFold, can predict with high accuracy folding proteins for which availability homology templates limited. Here we quantify effect recently released AlphaFold database structural models in our knowledge on human proteins. Our results indicate current baseline coverage 48%, considering experimentally-derived or template-based models, elevates up 76% when including predictions. At same time fraction dark proteome reduced from 26% just 10% are considered. Furthermore, although disease-associated genes and mutations was near complete before release (69% Clinvar pathogenic 88% oncogenic mutations), still provide an additional 3% 13% these critically important sets biomedical mutations. Finally, show how contribution non-human organisms, bacteria, significantly larger than proteome. Overall, sequence-structure gap has almost disappeared, outstanding success direct consequences genome derived medical applications.

Language: Английский

Therapeutic siRNA: State-of-the-Art and Future Perspectives DOI Creative Commons
Maik Friedrich, Achim Aigner

BioDrugs, Journal Year: 2022, Volume and Issue: 36(5), P. 549 - 571

Published: Aug. 23, 2022

The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after discovery interference mechanism, first siRNA drugs received approval for clinical use by US Food and Drug Administration European Medicines Agency between 2018 2022. These are mainly an conjugation with a targeting moiety liver hepatocytes, N-acetylgalactosamine, cover treatment acute hepatic porphyria, transthyretin-mediated amyloidosis, hypercholesterolemia, primary hyperoxaluria type 1. Still, development therapeutics faces several challenges issues, including definition optimal siRNAs in terms target, sequence, chemical modifications, delivery to its intended site action, absence unspecific off-target effects. Further studies, different systems covering wide range pathologies metabolic diseases, hematology, infectious oncology, ocular others. This article reviews knowledge design modification, as well issues related that may be addressed using systems. Details mode action status various provided, before giving outlook regarding future their potential one emerging standard modality pharmacotherapy. Notably, this also otherwise un-druggable non-coding targets, concepts personalized combination regimens.

Language: Английский

Citations

238
The era of reference genomes in conservation genomics DOI Creative Commons
Giulio Formenti, Kathrin Theißinger, Carlos Fernandes

et al.

Trends in Ecology & Evolution, Journal Year: 2022, Volume and Issue: 37(3), P. 197 - 202

Published: Jan. 24, 2022

Progress in genome sequencing now enables the large-scale generation of reference genomes. Various international initiatives aim to generate genomes representing global biodiversity. These provide unique insights into genomic diversity and architecture, thereby enabling comprehensive analyses population functional genomics, are expected revolutionize conservation genomics.

Language: Английский

Citations

234
MutationTaster2021 DOI Creative Commons
Robin Steinhaus, Sebastian Proft, Markus Schuelke

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(W1), P. W446 - W451

Published: April 1, 2021

Here we present an update to MutationTaster, our DNA variant effect prediction tool. The new version uses a different model and attains higher accuracy than its predecessor, especially for rare benign variants. In addition, have integrated many sources of data that only became available after the last release (such as gnomAD ExAC pLI scores) changed splice site model. To more easily assess relevance detected known disease mutations clinical phenotype patient, MutationTaster now provides information on diseases they cause. Further changes represent major overhaul interfaces increase user-friendliness whilst under hood been designed accelerate processing uploaded VCF files. We also offer API rapid automated query smaller numbers variants from within other software. MutationTaster2021 integrates mutation search engine, MutationDistiller, prioritise files using patient's phenotype. novel is at https://www.genecascade.org/MutationTaster2021/. This website free open all users there no login requirement.

Language: Английский

Citations

214
RNAInter v4.0: RNA interactome repository with redefined confidence scoring system and improved accessibility DOI Creative Commons
Juanjuan Kang, Qiang Tang, Jun He

et al.

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 50(D1), P. D326 - D332

Published: Oct. 9, 2021

Abstract Establishing an RNA-associated interaction repository facilitates the system-level understanding of RNA functions. However, as these interactions are distributed throughout various resources, essential prerequisite for effectively applying data requires that they deposited together and annotated with confidence scores. Hence, we have updated database RNAInter (RNA Interactome Database) to version 4.0, which is freely accessible at http://www.rnainter.org or http://www.rna-society.org/rnainter/. Compared previous versions, current not only contains enlarged set, but also scoring system. The merits this 4.0 can be summarized in following points: (i) a redefined system achieved by integrating trust experimental evidence, scientific community types tissues/cells, (ii) redesigned fully functional enables more rapid retrieval browsing via upgraded user-friendly interface (iii) update entries >47 million manually mining literature six resources evidence from computational sources. Overall, will provide comprehensive readily interactome platform investigate regulatory landscape cellular RNAs.

Language: Английский

Citations

168
Zebrafish information network, the knowledgebase for Danio rerio research DOI Creative Commons
Yvonne M. Bradford, Ceri E. Van Slyke, Leyla Ruzicka

et al.

Genetics, Journal Year: 2022, Volume and Issue: 220(4)

Published: Feb. 15, 2022

The Zebrafish Information Network (zfin.org) is the central repository for Danio rerio genetic and genomic data. has served zebrafish research community since 1994, expertly curating, integrating, displaying Key data types available at include, but are not limited to, genes, alleles, human disease models, gene expression, phenotype, function. makes Findable, Accessible, Interoperable, Reusable through nomenclature, curatorial annotation activities, web interfaces, downloads. Recently, 6 other model organism knowledgebases have collaborated to form Alliance of Genome Resources, aiming develop sustainable genome information resources that enable use organisms understand basis biology disease. Here, we provide an overview including recent updates page access single-cell RNA sequencing data, links pages, ribbon diagrams summarize biological systems Gene Ontology terms annotations, integration with Resources.

Language: Английский

Citations

166
AnimalTFDB 4.0: a comprehensive animal transcription factor database updated with variation and expression annotations DOI Creative Commons

Wen‐Kang Shen,

Si‐Yi Chen,

Zi-Quan Gan

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D39 - D45

Published: Oct. 5, 2022

Abstract Transcription factors (TFs) are proteins that interact with specific DNA sequences to regulate gene expression and play crucial roles in all kinds of biological processes. To keep up new data provide a more comprehensive resource for TF research, we updated the Animal Factor Database (AnimalTFDB) version 4.0 (http://bioinfo.life.hust.edu.cn/AnimalTFDB4/) up-to-date functions. We refined family rules prediction pipeline predict TFs genome-wide protein from Ensembl. As result, predicted 274 633 genes 150 726 transcription cofactor AnimalTFDB 183 animal genomes, which 86 species than 3.0. Besides double volume, also added following annotations functions database: (i) variations (including mutations) on various human cancers other diseases; (ii) post-translational modification sites phosphorylation, acetylation, methylation ubiquitination sites) 8 species; (iii) regulation autophagy; (iv) annotation 38 (v) exact batch search allow users flexibly. is useful studying regulation, contains classification cofactors.

Language: Английский

Citations

160
A Proximal-to-Distal Survey of Healthy Adult Human Small Intestine and Colon Epithelium by Single-Cell Transcriptomics DOI Creative Commons
Joseph Burclaff, R. Jarrett Bliton, Keith A. Breau

et al.

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2022, Volume and Issue: 13(5), P. 1554 - 1589

Published: Jan. 1, 2022

Background & AimsSingle-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell covering duodenum, jejunum, ileum, ascending, transverse, descending from 3 beings.MethodsA total 12,590 single epithelial cells independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, drug targets. Analyses focused on intrinsic cell properties their capacity response to extrinsic signals along gut axis across different beings.ResultsCells assigned 25 clusters. Multiple accepted intestinal stem markers do not specifically mark all cells. Lysozyme expression is unique Paneth cells, lack expected niche factors. Bestrophin 4 (BEST4)+ express Neuropeptide Y (NPY) show maturational differences between colon. Tuft possess a broad ability interact with innate adaptive immune systems through previously unreported receptors. Some classes mucins, hormones, junctions, nutrient absorption genes unappreciated regional lineages. The differential receptors targets lineages biological variation potential variegated responses.ConclusionsOur study identifies novel marker covers differences, shows important mouse epithelium, reveals insight into how epithelium responds environment drugs. This comprehensive atlas resolves likely functional anatomic regions gastrointestinal tract advances our understanding physiology. Single-cell beings. A Cells responses. Our

Language: Английский

Citations

150
Learning functional properties of proteins with language models DOI
Serbülent Ünsal, Heval Ataş, Muammer Albayrak

et al.

Nature Machine Intelligence, Journal Year: 2022, Volume and Issue: 4(3), P. 227 - 245

Published: March 21, 2022

Language: Английский

Citations

137
Multiomics study of nonalcoholic fatty liver disease DOI Creative Commons
Garðar Sveinbjörnsson, Magnús Ö. Úlfarsson, Rósa B. Þórólfsdóttir

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(11), P. 1652 - 1663

Published: Oct. 24, 2022

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis hepatocellular carcinoma, integrated the findings with expression proteomic data. For we utilized 9,491 clinical cases proton density fat fraction extracted from 36,116 magnetic resonance images. identified 18 sequence variants associated NAFL 4 cirrhosis, found rare, protective, predicted loss-of-function in MTARC1 GPAM, underscoring them as potential drug targets. leveraged messenger RNA expression, splicing coding effects to identify 16 putative causal genes, which many implicated lipid metabolism. analyzed levels 4,907 plasma proteins 35,559 Icelanders 1,459 47,151 UK Biobank participants, identifying multiple involved disease pathogenesis. show that proteomics can discriminate between cirrhosis. The present provides insights into development noninvasive evaluation new therapeutic options.

Language: Английский

Citations

137
Benchmarking challenging small variants with linked and long reads DOI Creative Commons
Justin Wagner, Nathan D. Olson, Lindsay Harris

et al.

Cell Genomics, Journal Year: 2022, Volume and Issue: 2(5), P. 100128 - 100128

Published: April 28, 2022

Genome in a Bottle benchmarks are widely used to help validate clinical sequencing pipelines and develop variant calling methods. Here we use accurate linked long reads expand 7 samples include difficult-to-map regions segmental duplications that challenging for short reads. These add more than 300,000 SNVs 50,000 insertions or deletions (indels) 16% exonic variants, many challenging, clinically relevant genes not covered previously, such as PMS2. For HG002, 92% of the autosomal GRCh38 assembly while excluding problematic benchmarking small copy number should have been previous version, which included 85% GRCh38. It identifies eight times false negatives read call set relative our benchmark. We demonstrate this benchmark reliably positives across technologies, enabling ongoing methods development.

Language: Английский

Citations

136