Co-expression networks reveal the tissue-specific regulation of transcription and splicing
- Ashis Saha1,
- Yungil Kim1,6,
- Ariel D.H. Gewirtz2,6,
- Brian Jo2,
- Chuan Gao3,
- Ian C. McDowell4,
- The GTEx Consortium7,
- Barbara E. Engelhardt5 and
- Alexis Battle1
- 1Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21218, USA;
- 2Program in Quantitative and Computational Biology, Princeton University, Princeton, New Jersey 08540, USA;
- 3Department of Statistical Science, Duke University, Durham, North Carolina 27708, USA;
- 4Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina 27708, USA;
- 5Department of Computer Science and Center for Statistics and Machine Learning, Princeton University, Princeton, New Jersey 08540, USA
- 8The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- 9Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA
- 10Massachusetts General Hospital Cancer Center and Dept. of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
- 11Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
- 12Department of Genetics, Stanford University, Stanford, CA 94305, USA
- 13Department of Pathology, Stanford University, Stanford, CA 94305, USA
- 14Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
- 15Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA
- 16Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain
- 17Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
- 18Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland
- 19Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
- 20Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland
- 21Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 22New York Genome Center, New York, NY 10013, USA
- 23Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
- 24Department of Public Health Sciences, The University of Chicago, Chicago, IL 60637, USA
- 25McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA
- 26Department of Genetics, Washington University School of Medicine, St. Louis, MO 63108, USA
- 27Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63108, USA
- 28Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- 29Department of Computer Science, Center for Statistics and Machine Learning, Princeton University, Princeton, NJ 08540, USA
- 30Department of Computer Science, University of California, Los Angeles, CA 90095, USA
- 31Department of Human Genetics, University of California, Los Angeles, CA 90095, USA
- 32Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal
- 33Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-625 Porto, Portugal
- 34Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- 35Department of Psychiatry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
- 36Lewis Sigler Institute, Princeton University, Princeton, NJ 08540, USA
- 37Department of Operations Research and Financial Engineering, Princeton University, Princeton, NJ 08540, USA
- 38Biomedical Informatics Program, Stanford University, Stanford, CA 94305, USA
- 39Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain
- 40Department of Medicine, Washington University School of Medicine, St. Louis, MO 63108, USA
- 41Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea
- 42Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
- 43Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
- 44Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
- 45Department of Biology, Stanford University, Stanford, CA 94305, USA
- 46Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK
- 47Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK
- 48Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LJ, UK
- 49Computational Biology & Bioinformatics Graduate Program, Duke University, Durham, NC 27708, USA
- 50Human Genetics Department, McGill University, Montreal, Quebec H3A 0G1, Canada
- 51Departament d'Estadística i Investigació Operativa, Universitat Politècnica de Catalunya, 08034 Barcelona, Spain
- 52Department of Statistics, The University of Chicago, Chicago, IL 60637, USA
- 53Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
- 54Department of Statistics and Operations Research, University of North Carolina, Chapel Hill, NC 27599, USA
- 55Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27599, USA
- 56Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA
- 57Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 58Computational Sciences, Pfizer Inc, Cambridge, MA 02139, USA
- 59Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
- 60Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA
- 61Department of Statistics, Stanford University, Stanford, CA 94305, USA
- 62Institute of Biophysics Carlos Chagas Filho (IBCCF), Federal University of Rio de Janeiro (UFRJ), 21941902 Rio de Janeiro, Brazil
- 63Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA
- 64Center for Data Intensive Science, The University of Chicago, Chicago, IL 60637, USA
- 65Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA
- 66Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA
- 67Bioinformatics Research Center and Departments of Statistics and Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA
- 68National Institute for Biotechnology in the Negev, Beer-Sheva, 84105 Israel
- 69European Molecular Biology Laboratory, 69117 Heidelberg, Germany
- 70Department of Ecology and Evolutionary Biology, Princeton University, Princeton, NJ 08540, USA
- 71Altius Institute for Biomedical Sciences, Seattle, WA 98121, USA
- 72Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
- 73University of Hohenheim, 70599 Stuttgart, Germany
- 74Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112-5550, USA
- 75Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- 76Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- 77Department of Mental Health, Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA
- 78McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
- 79Department of Biostatistics, Johns Hopkins University, Baltimore, MD 21205, USA
- 80Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- 81Department of Medicine, University of Washington, Seattle, WA 98195, USA
- 82Division of Cardiology, University of Washington, Seattle, WA 98195, USA
- 83Institute for Systems Genetics, New York University Langone Medical Center, New York, NY 10016, USA
- 84Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
- 85Office of Strategic Coordination, Division of Program Coordination, Planning and Strategic Initiatives, Office of the Director, NIH, Rockville, MD 20852, USA
- 86Biorepositories and Biospecimen Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA
- 87National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA
- 88Division of Genomic Medicine, National Human Genome Research Institute, Rockville, MD 20852, USA
- 89Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA
- 90Division of Neuroscience and Behavior, National Institute on Drug Abuse, NIH, Bethesda, MD 20892, USA
- 91Washington Regional Transplant Community, Falls Church, VA 22003, USA
- 92Gift of Life Donor Program, Philadelphia, PA 19103, USA
- 93LifeGift, Houston, TX 77055, USA
- 94Center for Organ Recovery and Education, Pittsburgh, PA 15238, USA
- 95LifeNet Health, Virginia Beach, VA 23453, USA
- 96National Disease Research Interchange, Philadelphia, PA 19103, USA
- 97Unyts, Buffalo, NY 14203, USA
- 98Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- 99Van Andel Research Institute, Grand Rapids, MI 49503, USA
- 100Brain Endowment Bank, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- 101National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
- 102Biospecimen Research Group, Clinical Research Directorate, Leidos Biomedical Research, Inc., Rockville, MD 20852, USA
- 103Leidos Biomedical Research, Inc., Frederick, MD 21701, USA
- 104Temple University, Philadelphia, PA 19122, USA
- 105Department of Health Behavior and Policy, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- 106European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SD, UK
- 107UCSC Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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↵6 These authors contributed equally to this work.
Abstract
Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.
Footnotes
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↵7 A full list of GTEx Consortium members is available at the end of the text.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.216721.116.
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Freely available online through the Genome Research Open Access option.
- Received September 30, 2016.
- Accepted August 22, 2017.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
