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

Khurana, E., Fu, Y., Colonna, V., Mu, X. J., Kang, H. M., Lappalainen, T., Sboner, A., Lochovsky, L., Chen, J., Harmanci, A., Das, J., Abyzov, A., Balasubramanian, S., Beal, K., Chakravarty, D., Challis, D., Chen, Y., Clarke, D., Clarke, L., Cunningham, F., Evani, U. S., Flicek, P., Fragoza, R., Garrison, E., Gibbs, R., Gumus, Z. H., Herrero, J., Kitabayashi, N., Kong, Y., Lage, K., Liluashvili, V., Lipkin, S. M., MacArthur, D. G., Marth, G., Muzny, D., Pers, T. H., Ritchie, G. R. S., Rosenfeld, J. A., Sisu, C., Wei, X., Wilson, M., Xue, Y., Yu, F., Dermitzakis, E. T., Yu, H., Rubin, M. A., Tyler-Smith, C., Gerstein, M., Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and 1000 Genomes Project Consortium 2013. Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 342 (6154) , 1235587. 10.1126/science.1235587

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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

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Additional Information:	David Cooper is a participant in the 1000 Genomes Project Consortium
Publisher:	American Association for the Advancement of Science
ISSN:	0036-8075
Last Modified:	31 Oct 2022 10:12
URI:	https://orca.cardiff.ac.uk/id/eprint/84059

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