دورية أكاديمية
أعرض في EDS

MTR3D: identifying regions within protein tertiary structures under purifying selection.

التفاصيل البيبلوغرافية
العنوان: MTR3D: identifying regions within protein tertiary structures under purifying selection.
المؤلفون: Silk M; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia.; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Melbourne, Australia.; Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Australia., Pires DEV; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia.; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Melbourne, Australia.; Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Australia.; School of Computing and Information Systems, University of Melbourne, Melbourne, Australia., Rodrigues CHM; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia.; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Melbourne, Australia.; Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Australia., D'Souza EN; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia.; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Melbourne, Australia.; Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Australia., Olshansky M; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia., Thorne N; Melbourne Genomics Health Alliance, Melbourne, Australia., Ascher DB; Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Australia.; Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Melbourne, Australia.; Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Australia.; Department of Biochemistry, University of Cambridge, Cambridge, UK.
المصدر: Nucleic acids research [Nucleic Acids Res] 2021 Jul 02; Vol. 49 (W1), pp. W438-W445.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Validation Study
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE
أسماء مطبوعة: Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.
مواضيع طبية MeSH: Mutation, Missense* , Software*, Protein Structure, Tertiary/*genetics, Genomics ; Humans ; Neoplasms/genetics ; Structural Homology, Protein
مستخلص: The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome sequences to over 81,000 experimental structures and homology models of the human proteome, we have calculated both regional intolerance to missense variation (Missense Tolerance Ratio, MTR), using a sliding window of 21-41 codons, and introduce a new 3D spatial intolerance to missense variation score (3D Missense Tolerance Ratio, MTR3D), using spheres of 5-8 Å. We show that the MTR3D is less biased by regions with limited data and more accurately identifies regions under purifying selection than estimates relying on the sequence alone. Intolerant regions were highly enriched for both ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P < 2.2 × 10-16). Further, we combine sequence- and spatial-based scores to generate a consensus score, MTRX, which distinguishes pathogenic from benign variants more accurately than either score separately (AUC = 0.85). The MTR3D server enables easy visualisation of population variation, MTR, MTR3D and MTRX scores across the entire gene and protein structure for >17,000 human genes and >42,000 alternative alternate transcripts, including both Ensembl and RefSeq transcripts. MTR3D is freely available by user-friendly web-interface and API at http://biosig.unimelb.edu.au/mtr3d/.
(© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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معلومات مُعتمدة: United Kingdom Wellcome Trust; MR/M026302/1 United Kingdom MRC_ Medical Research Council; 200814/Z/16/Z United Kingdom WT_ Wellcome Trust
تواريخ الأحداث: Date Created: 20210529 Date Completed: 20210720 Latest Revision: 20220129
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8265191
DOI: 10.1093/nar/gkab428
PMID: 34050760
قاعدة البيانات: MEDLINE
الوصف
تدمد:1362-4962
DOI:10.1093/nar/gkab428