دورية أكاديمية
Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics
| العنوان: | Integrative Annotation of Variants from 1092 Humans: Application to Cancer Genomics |
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| المؤلفون: | Khurana, E, Fu, Y, Colonna, V, Mu, XJ, Kang, HM, 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, US, Flicek, P, Fragoza, R, Garrison, E, Gibbs, R, Guemues, ZH, Herrero, J, Kitabayashi, N, Kong, Y, Lage, K, Liluashvili, V, Lipkin, SM, MacArthur, DG, Marth, G, Muzny, D, Pers, TH, Ritchie, GRS, Rosenfeld, JA, Sisu, C, Wei, X, Wilson, M, Xue, Y, Yu, F, Dermitzakis, ET, Yu, H, Rubin, MA, Tyler-Smith, C, Gerstein, M |
| بيانات النشر: | AMER ASSOC ADVANCEMENT SCIENCE |
| سنة النشر: | 2013 |
| المجموعة: | Brunel University London: Brunel University Research Archive (BURA) |
| مصطلحات موضوعية: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, TERT PROMOTER MUTATIONS, NATURAL-SELECTION, PROSTATE-CANCER, POSITIVE SELECTION, GENETIC-VARIATION, HUMAN-EVOLUTION, COPY NUMBER, ELEMENTS, NETWORK, DISEASE |
| الوصف: | Introduction: Plummeting sequencing costs have led to a great increase in the number of personal genomes. Interpreting the large number of variants in them, particularly in noncoding regions, is a current challenge. This is especially the case for somatic variants in cancer genomes, a large proportion of which are noncoding. Methods: We investigated patterns of selection in DNA elements from the ENCODE project using the full spectrum of variants from 1092 individuals in the 1000 Genomes Project (Phase 1), including single-nucleotide variants (SNVs), short insertions and deletions (indels), and structural variants (SVs). Although we analyzed broad functional annotations, such as all transcription-factor binding sites, we focused more on highly specifi c categories such as distal binding sites of factor ZNF274. The greater statistical power of the Phase 1 data set compared with earlier ones allowed us to differentiate the selective constraints on these categories. We also used connectivity information between elements from protein-protein-interaction and regulatory networks. We integrated all the information on selection to develop a workfl ow (FunSeq) to prioritize personal-genome variants on the basis of their deleterious impact. As a proof of principle, we experimentally validated and characterized a few candidate variants. Results: We identifi ed a specifi c subgroup of noncoding categories with almost as much selective constraint as coding genes: “ultrasensitive” regions. We also uncovered a number of clear patterns of selection. Elements more consistently active across tissues and both maternal and paternal alleles (in terms of allele-specifi c activity) are under stronger selection. Variants disruptive because of mechanistic effects on transcription-factor binding (i.e. “motif-breakers”) are selected against. Higher network connectivity (i.e. for hubs) is associated with higher constraint. Additionally, many hub promoters and regulatory elements show evidence of recent positive selection. Overall, indels ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | 84 - + (10) |
| اللغة: | English |
| تدمد: | 0036-8075 1095-9203 |
| العلاقة: | SCIENCE; SCIENCE, 2013, 342 (6154), pp. 84 - + (10); http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000325126100049&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=f12c8c83318cf2733e615e54d9ed7ad5Test; ARTN 1235587; http://bura.brunel.ac.uk/handle/2438/14923Test; http://dx.doi.org/10.1126/science.1235587Test |
| DOI: | 10.1126/science.1235587 |
| الإتاحة: | https://doi.org/10.1126/science.1235587Test http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000325126100049&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=f12c8c83318cf2733e615e54d9ed7ad5Test http://bura.brunel.ac.uk/handle/2438/14923Test |
| رقم الانضمام: | edsbas.9271BA2B |
| قاعدة البيانات: | BASE |
| تدمد: | 00368075 10959203 |
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| DOI: | 10.1126/science.1235587 |