{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T07:48:31Z","timestamp":1778226511263,"version":"3.51.4"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"W1","license":[{"start":{"date-parts":[[2019,6,6]],"date-time":"2019-06-06T00:00:00Z","timestamp":1559779200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["1126877"],"award-info":[{"award-number":["1126877"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012698","name":"Jack Brockhoff Foundation","doi-asserted-by":"publisher","award":["JBF 4186"],"award-info":[{"award-number":["JBF 4186"]}],"id":[{"id":"10.13039\/100012698","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/M026302\/1"],"award-info":[{"award-number":["MR\/M026302\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1072476"],"award-info":[{"award-number":["APP1072476"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u00a0000 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\u2013Whitney U test P &lt; 2.2 \u00d7 10\u221216). 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 http:\/\/biosig.unimelb.edu.au\/mtr-viewer\/.<\/jats:p>","DOI":"10.1093\/nar\/gkz457","type":"journal-article","created":{"date-parts":[[2019,6,3]],"date-time":"2019-06-03T15:11:24Z","timestamp":1559574684000},"page":"W121-W126","source":"Crossref","is-referenced-by-count":67,"title":["MTR-Viewer: identifying regions within genes under purifying selection"],"prefix":"10.1093","volume":"47","author":[{"given":"Michael","family":"Silk","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne,\u00a0VIC\u00a03052, Australia"},{"name":"ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne,\u00a0Melbourne,\u00a0VIC\u00a03052, Australia"},{"name":"Structural Biology and Bioinformatics, Baker Heart and Diabetes Institute, Melbourne, VIC\u00a03004, Australia"}]},{"given":"Slav\u00e9","family":"Petrovski","sequence":"additional","affiliation":[{"name":"Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, UK"},{"name":"Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC\u00a03050, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-2413","authenticated-orcid":false,"given":"David B","family":"Ascher","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne,\u00a0VIC\u00a03052, Australia"},{"name":"ACRF Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne,\u00a0Melbourne,\u00a0VIC\u00a03052, Australia"},{"name":"Structural Biology and Bioinformatics, Baker Heart and Diabetes Institute, Melbourne, VIC\u00a03004, Australia"},{"name":"Department of Biochemistry, University of Cambridge; Cambridge CB2 1GA, UK"}]}],"member":"286","published-online":{"date-parts":[[2019,6,6]]},"reference":[{"key":"2019062808325162600_B1","doi-asserted-by":"crossref","first-page":"19096","DOI":"10.1073\/pnas.0910672106","article-title":"Genetic diagnosis by whole exome capture and massively parallel DNA sequencing","volume":"106","author":"Choi","year":"2009","journal-title":"Proc. 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Mutat."},{"key":"2019062808325162600_B7","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"2019062808325162600_B8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2019062808325162600_B9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Genomes Project, C.","year":"2015","journal-title":"Nature"},{"key":"2019062808325162600_B10","doi-asserted-by":"crossref","first-page":"e1003709","DOI":"10.1371\/journal.pgen.1003709","article-title":"Genic intolerance to functional variation and the interpretation of personal genomes","volume":"9","author":"Petrovski","year":"2013","journal-title":"PLos Genet."},{"key":"2019062808325162600_B11","doi-asserted-by":"crossref","DOI":"10.1101\/148353","article-title":"Regional missense constraint improves variant deleteriousness prediction","author":"Samocha","year":"2017"},{"key":"2019062808325162600_B12","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1101\/gr.226589.117","article-title":"Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation","volume":"27","author":"Traynelis","year":"2017","journal-title":"Genome Res."},{"key":"2019062808325162600_B13","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1126\/science.aaf6814","article-title":"Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study","volume":"354","author":"Dewey","year":"2016","journal-title":"Science"},{"key":"2019062808325162600_B14","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med."},{"key":"2019062808325162600_B15","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"2019062808325162600_B16","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: open software development for computational biology and bioinformatics","volume":"5","author":"Gentleman","year":"2004","journal-title":"Genome Biol."},{"key":"2019062808325162600_B17","doi-asserted-by":"crossref","first-page":"D619","DOI":"10.1093\/nar\/gkw1033","article-title":"Genenames.org: the HGNC and VGNC resources in 2017","volume":"45","author":"Yates","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2019062808325162600_B18","doi-asserted-by":"crossref","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation","volume":"44","author":"O\u2019Leary","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2019062808325162600_B19","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2019062808325162600_B20","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41568-018-0060-1","article-title":"The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers","volume":"18","author":"Sondka","year":"2018","journal-title":"Nat. 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