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Title: MTR-Viewer: identifying regions within genes under purifying selection.
Austin Authors: Silk, Michael;Petrovski, Slavé;Ascher, David B
Affiliation: Department of Biochemistry, University of Cambridge; Cambridge CB2 1GA, UK
Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, UK
Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC 3052, Australia
ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne, Melbourne, VIC 3052, Australia
Structural Biology and Bioinformatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Issue Date: 6-Jun-2019 2019-07-02
Publication information: Nucleic acids research 2019; 47(W1): W121-W126
Abstract: Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present the MTR-Viewer, a web-server enabling easy visualization at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 240 000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18 000 human protein-coding genes and 85 000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein's domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P < 2.2 × 10-16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at
DOI: 10.1093/nar/gkz457
ORCID: 0000-0002-1527-961X
PubMed URL: 31170280
Type: Journal Article
Appears in Collections:Journal articles

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