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Integrative annotation of variants from 1092 humans: application to cancer genomics

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Published in Science. 2013, vol. 342, no. 6154, p. 1235587
Abstract Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations ("ultrasensitive") and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, "motif-breakers"). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.
Keywords Binding Sites/geneticsGenetic VariationGenome, HumanGenomicsHumansKruppel-Like Transcription Factors/metabolismMolecular Sequence Annotation/methodsMutationNeoplasms/geneticsPolymorphism, Single NucleotidePopulation/geneticsRNA, Untranslated/geneticsSelection, Genetic
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PMID: 24092746
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Research group Population Genomics and Genetics of Complex Traits (892)
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LAPPALAINEN, Tuuli Emilia, DERMITZAKIS, Emmanouil. Integrative annotation of variants from 1092 humans: application to cancer genomics. In: Science, 2013, vol. 342, n° 6154, p. 1235587. https://archive-ouverte.unige.ch/unige:90279

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Deposited on : 2016-12-13

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