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      A Statistical Framework to Predict Functional Non-Coding Regions in the Human Genome Through Integrated Analysis of Annotation Data

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          Abstract

          Identifying functional regions in the human genome is a major goal in human genetics. Great efforts have been made to functionally annotate the human genome either through computational predictions, such as genomic conservation, or high-throughput experiments, such as the ENCODE project. These efforts have resulted in a rich collection of functional annotation data of diverse types that need to be jointly analyzed for integrated interpretation and annotation. Here we present GenoCanyon, a whole-genome annotation method that performs unsupervised statistical learning using 22 computational and experimental annotations thereby inferring the functional potential of each position in the human genome. With GenoCanyon, we are able to predict many of the known functional regions. The ability of predicting functional regions as well as its generalizable statistical framework makes GenoCanyon a unique and powerful tool for whole-genome annotation. The GenoCanyon web server is available at http://genocanyon.med.yale.edu

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          Most cited references33

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          Gene action in the X-chromosome of the mouse (Mus musculus L.).

          MARY LYON (1961)
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            Defining functional DNA elements in the human genome.

            With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.
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              Interpreting non-coding variation in complex disease genetics

              Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has primarily focused on protein-coding variants, due to the difficulty of interpreting non-coding mutations. This picture has changed with advances in the systematic annotation of functional non-coding elements. Evolutionary conservation, functional genomics, chromatin state, sequence motifs, and molecular quantitative trait loci all provide complementary information about non-coding function. These functional maps can help prioritize variants on risk haplotypes, filter mutations encountered in the clinic, and perform systems-level analyses to reveal processes underlying disease associations. Advances in predictive modeling can enable dataset integration to reveal pathways shared across loci and alleles, and richer regulatory models can guide the search for epistatic interactions. Lastly, new massively parallel reporter experiments can systematically validate regulatory predictions. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis, and treatment.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                27 May 2015
                2015
                : 5
                : 10576
                Affiliations
                [1 ]Department of Biostatistics, Yale School of Public Health , New Haven, CT, USA
                [2 ]Program of Computational Biology and Bioinformatics, Yale University , New Haven, CT, USA
                [3 ]Yale Center for Medical Informatics, Yale School of Medicine , New Haven, CT, USA
                [4 ]Department of Emergency Medicine, Yale School of Medicine , New Haven, CT, USA
                [5 ]VA Connecticut Healthcare System , West Haven, CT, USA
                Author notes
                Article
                srep10576
                10.1038/srep10576
                4444969
                26015273
                0a16a8c5-8952-415a-bfef-1e7a9e32c38b
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 16 December 2014
                : 20 April 2015
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