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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...

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Detalles Bibliográficos
Autores principales: Cheng, Si-Jin, Shi, Fang-Yuan, Liu, Huan, Ding, Yang, Jiang, Shuai, Liang, Nan, Gao, Ge
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
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
Descripción
Sumario: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.