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Accurately annotate compound effects of genetic variants using a context-sensitive framework
In genomics, effectively identifying the biological effects of genetic variants is crucial. Current methods handle each variant independently, assuming that each variant acts in a context-free manner. However, variants within the same gene may interfere with each other, producing combinational (comp...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449550/ https://www.ncbi.nlm.nih.gov/pubmed/28158838 http://dx.doi.org/10.1093/nar/gkx041 |
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author | Cheng, Si-Jin Shi, Fang-Yuan Liu, Huan Ding, Yang Jiang, Shuai Liang, Nan Gao, Ge |
author_facet | Cheng, Si-Jin Shi, Fang-Yuan Liu, Huan Ding, Yang Jiang, Shuai Liang, Nan Gao, Ge |
author_sort | Cheng, Si-Jin |
collection | PubMed |
description | In genomics, effectively identifying the biological effects of genetic variants is crucial. Current methods handle each variant independently, assuming that each variant acts in a context-free manner. However, variants within the same gene may interfere with each other, producing combinational (compound) rather than individual effects. In this work, we introduce COPE, a gene-centric variant annotation tool that integrates the entire sequential context in evaluating the functional effects of intra-genic variants. Applying COPE to the 1000 Genomes dataset, we identified numerous cases of multiple-variant compound effects that frequently led to false-positive and false-negative loss-of-function calls by conventional variant-centric tools. Specifically, 64 disease-causing mutations were identified to be rescued in a specific genomic context, thus potentially contributing to the buffering effects for highly penetrant deleterious mutations. COPE is freely available for academic use at http://cope.cbi.pku.edu.cn. |
format | Online Article Text |
id | pubmed-5449550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54495502017-06-05 Accurately annotate compound effects of genetic variants using a context-sensitive framework Cheng, Si-Jin Shi, Fang-Yuan Liu, Huan Ding, Yang Jiang, Shuai Liang, Nan Gao, Ge Nucleic Acids Res Methods Online In genomics, effectively identifying the biological effects of genetic variants is crucial. Current methods handle each variant independently, assuming that each variant acts in a context-free manner. However, variants within the same gene may interfere with each other, producing combinational (compound) rather than individual effects. In this work, we introduce COPE, a gene-centric variant annotation tool that integrates the entire sequential context in evaluating the functional effects of intra-genic variants. Applying COPE to the 1000 Genomes dataset, we identified numerous cases of multiple-variant compound effects that frequently led to false-positive and false-negative loss-of-function calls by conventional variant-centric tools. Specifically, 64 disease-causing mutations were identified to be rescued in a specific genomic context, thus potentially contributing to the buffering effects for highly penetrant deleterious mutations. COPE is freely available for academic use at http://cope.cbi.pku.edu.cn. Oxford University Press 2017-06-02 2017-02-01 /pmc/articles/PMC5449550/ /pubmed/28158838 http://dx.doi.org/10.1093/nar/gkx041 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Methods Online Cheng, Si-Jin Shi, Fang-Yuan Liu, Huan Ding, Yang Jiang, Shuai Liang, Nan Gao, Ge Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title | Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title_full | Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title_fullStr | Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title_full_unstemmed | Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title_short | Accurately annotate compound effects of genetic variants using a context-sensitive framework |
title_sort | accurately annotate compound effects of genetic variants using a context-sensitive framework |
topic | Methods Online |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449550/ https://www.ncbi.nlm.nih.gov/pubmed/28158838 http://dx.doi.org/10.1093/nar/gkx041 |
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