Search and sequence analysis tools services from EMBL-EBI in 2022

Nucleic Acids Research, Год журнала: 2022, Номер 50(W1), С. W276 - W279

Опубликована: Март 28, 2022

Abstract The EMBL-EBI search and sequence analysis tools frameworks provide integrated access to EMBL-EBI’s data resources core bioinformatics analytical tools. EBI Search (https://www.ebi.ac.uk/ebisearch) provides a full-text engine across nearly 5 billion entries, while the Job Dispatcher framework (https://www.ebi.ac.uk/services) enables scientific community perform diverse range of using popular applications. Both allow users interact through user-friendly web applications, as well via RESTful SOAP-based APIs. Here, we describe recent improvements these services updates made accommodate increasing requirements during COVID-19 pandemic.

Язык: Английский

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Omicron and Delta variant of SARS‐CoV‐2: A comparative computational study of spike protein

Journal of Medical Virology, Год журнала: 2021, Номер 94(4), С. 1641 - 1649

Опубликована: Дек. 16, 2021

Abstract Emerging severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) variants, especially those of concern, may have an impact on the virus's transmissibility and pathogenicity, as well diagnostic equipment performance vaccine effectiveness. Even though SARS‐CoV‐2 Delta variant (B.1.617.2) emerged during India's second wave infections, variants grown dominant internationally are still evolving. On November 26, 2021, World Health Organization identified B.1.1.529 a naming it Omicron, based evidence that Omicron contains numerous mutations influence its behavior. However, mode transmission severity remains unknown. We used computational studies to examine in this study found had higher affinity for human angiotensin‐converting enzyme (ACE2) than due significant number receptor‐binding domain (RBD), indicating potential transmission. Based docking studies, Q493R, N501Y, S371L, S373P, S375F, Q498R, T478K contribute significantly high binding with ACE2. In comparison variant, both entire spike protein RBD include proportion hydrophobic amino acids such leucine phenylalanine. These located within protein's core required structural stability. observed disorder–order transition between regions 468–473, be disordered residues/regions stability A future might investigate epidemiological biological consequences variant.

Язык: Английский

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Genetic and chemotherapeutic influences on germline hypermutation

Nature, Год журнала: 2022, Номер 605(7910), С. 503 - 508

Опубликована: Май 11, 2022

Abstract Mutations in the germline generates all evolutionary genetic variation and is a cause of disease. Parental age primary determinant number new mutations an individual’s genome 1,2 . Here we analysed genome-wide sequences 21,879 families with rare diseases identified 12 individuals hypermutated between two seven times more de novo single-nucleotide variants than expected. In most (9 out 12), excess came from father. Two had drivers hypermutation, fathers carrying damaging DNA-repair genes. For five families, paternal exposure to chemotherapeutic agents before conception was probably key driver hypermutation. Our results suggest that well protected mutagenic effects, hypermutation rare, relatively modest will not have

Язык: Английский

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VarSite: Disease variants and protein structure

Protein Science, Год журнала: 2019, Номер 29(1), С. 111 - 119

Опубликована: Окт. 13, 2019

VarSite is a web server mapping known disease-associated variants from UniProt and ClinVar, together with natural gnomAD, onto protein 3D structures in the Protein Data Bank. The analyses are primarily image-based provide both an overview for each human protein, as well report any specific variant of interest. information can be useful assessing whether given might pathogenic or benign. structural annotations position include secondary structure, interactions ligand, metal, DNA/RNA, other various measures variant's possible impact on protein's function. locations viewed interactively via 3dmol.js JavaScript viewer, RasMol PyMOL. Users search variants, sets by providing DNA coordinates base change(s) Additionally, agglomerative given, such disease Pfam CATH domains. freely accessible to all at: https://www.ebi.ac.uk/thornton-srv/databases/VarSite.

Язык: Английский

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Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(45), С. 28201 - 28211

Опубликована: Окт. 26, 2020

Significance Recent large-scale sequencing efforts have enabled the detection of millions missense variants. Elucidating their functional effect is crucial importance but challenging. We approach this problem by performing a wide-scale characterization variants from 1,330 disease-associated genes using >14,000 protein structures. identify 3D features associated with pathogenic and benign that unveiled mutations’ at molecular level. further extend our analysis to account for different essential structural regions in proteins functions. By analyzing 24 gene groups encoding families, we capture function-specific characteristics variants, which match experimental readouts. show results derived data will effectively inform variant interpretation.

Язык: Английский

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Omicron and Delta Variant of SARS-CoV-2: A Comparative Computational Study of Spike protein

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Дек. 3, 2021

Abstract Emerging SARS-CoV-2 variants, especially those of concern, may have an impact on the virus’s transmissibility and pathogenicity, as well diagnostic equipment performance vaccine effectiveness. Even though Delta variant (B.1.617.2) emerged during India’s second wave infections, variants grown dominant internationally are still evolving. On November 26, 2021, WHO identified B.1.1.529 a naming it Omicron, based evidence that Omicron contains numerous mutations influence its behaviour. However, mode transmission severity remains unknown. We used computational studies to examine in this work found had higher affinity for human ACE2 than due significant number receptor binding domain, indicating potential transmission. Based docking studies, Q493R, N501Y, S371L, S373P, S375F, Q498R, T478K contribute significantly high with ACE2. In comparison variant, both entire spike protein RBD include proportion hydrophobic amino acids such leucine phenylalanine. These located within protein’s core required structural stability. has percentage alpha-helix structure whole RBD, more stable structure. observed disorder-order transition between regions 468-473, be disordered residues/regions stability A future study might investigate epidemiological biological consequences variant.

Язык: Английский

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PDBsum extras: SARS‐CoV‐2 and AlphaFold models

Protein Science, Год журнала: 2021, Номер 31(1), С. 283 - 289

Опубликована: Ноя. 15, 2021

The PDBsum web server provides structural analyses of the entries in Protein Data Bank (PDB). Two recent additions are described here. first is detailed analysis SARS-CoV-2 virus protein structures PDB. These include variants concern, which shown both on sequences and 3D proteins. second addition inclusion available AlphaFold models for human pages allow a search against existing PDB via Sequence Annotated by Structure (SAS) server, so one can easily compare predicted model experimentally determined structures. freely accessible to all at http://www.ebi.ac.uk/pdbsum.

Язык: Английский

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ProtVar: mapping and contextualizing human missense variation

Nucleic Acids Research, Год журнала: 2024, Номер 52(W1), С. W140 - W147

Опубликована: Май 20, 2024

Abstract Genomic variation can impact normal biological function in complex ways and so understanding variant effects requires a broad range of data to be coherently assimilated. Whilst the volume human relevant annotations has increased, corresponding increase breadth participating fields, standards versioning mean that moving between genomic, coding, protein structure positions is increasingly complex. In turn this makes investigating variants diverse formats assimilating from different resources challenging. ProtVar addresses these issues facilitate contextualization interpretation missense with unparalleled flexibility ease accessibility for use by broadest researchers. By precalculating all possible proteome it offers near instantaneous mapping types. It also combines analyses plethora bring together sequence as well structural insights predictions better understand likely effect humans. offered an intuitive web server https://www.ebi.ac.uk/protvar where explored downloaded, accessed programmatically via API.

Язык: Английский

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De novo GABRA1 variants in childhood epilepsies and the molecular subregional effects

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Янв. 10, 2024

Background The GABRA1 gene, encoding the GABR A R subunit α1, plays vital roles in inhibitory neurons. Previously, gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) idiopathic generalized epilepsy (IGE). This study aims explore phenotypic spectrum of molecular subregional effect analysis. Methods Trios-based whole-exome sequencing was performed patients epilepsy. Previously reported mutations were systematically reviewed analyze effects. Results De novo six unrelated heterogeneous epilepsy, including three missense (p.His83Asn, p.Val207Phe, p.Arg214Cys) one frameshift mutation (p.Thr453Hisfs*47). two mutations, p.His83Asn predicted decrease protein stability but no hydrogen bond alteration, which also presented mild genetic febrile seizures plus achieved seizure-free status by monotherapy. variant p.Arg214Cys destroy bonds surrounding residues, recurrently cases severe DEE. p.Thr453Hisfs*47 located last fifth residue C-terminus caused an extension 47 amino acids, moderated tonic-clonic alone (GTCA) four drugs. variants not gnomAD evaluated as “pathogenic/likely pathogenic” according ACMG criteria. Analysis all indicated that N-terminal extracellular region a significantly higher percentage FS DEE, transmembrane earlier seizure onset ages. Significance suggested potentially epilepsies, EFS+, GTCA. Phenotypic severity may damaging variants. effects help understanding underlying mechanism variation.

Язык: Английский

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DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Янв. 5, 2024

Background The DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, has been identified as causative X-linked intellectual developmental disorder—90 (XLID-90; OMIM# 300850). This study aims to explore phenotypic spectrum and genotype-phenotype correlation. Methods Trios-based whole-exome sequencing was performed patients with epilepsy unknown causes. To analyze correlations, previously reported variants were systematically reviewed. Results seven unrelated cases epilepsy. These had no hemizygous frequencies controls. All predicted be damaging by silico tools alter hydrogen bonds surrounding residues and/or stability. Four mainly presented generalized seizures, including tonic-clonic myoclonic other three exhibited secondary seizures focal seizures. Multifocal discharges recorded all during electroencephalography monitoring, four initially but multifocal after drug treating. Protein-protein interaction network analysis revealed that interacts 52 genes high confidence, majority disease-causing associated a wide neurodevelopmental disorder (NDD) Three locating outside functional domains achieved seizure-free, while poor control Analysis non-null higher percentages than those null variants, suggesting Significance suggested with/without NDD, expanding . observed correlation potentially contributes understanding underlying mechanisms driving variation.

Язык: Английский

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