New Results
Multi-tissue integrative analysis of personal epigenomes
Joel Rozowsky, Jorg Drenkow, Yucheng T Yang, Gamze Gursoy, Timur Galeev, Beatrice Borsari, Charles B Epstein, Kun Xiong, Jinrui Xu, Jiahao Gao, Keyang Yu, Ana Berthel, Zhanlin Chen, Fabio Navarro, Jason Liu, Maxwell S Sun, James Wright, Justin Chang, Christopher JF Cameron, Noam Shoresh, Elizabeth Gaskell, Jessika Adrian, Sergey Aganezov, Gabriela Balderrama-Gutierrez, Samridhi Banskota, Guillermo Barreto Corona, Sora Chee, Surya B Chhetri, Gabriel Conte Cortez Martins, Cassidy Danyko, Carrie A Davis, Daniel Farid, Nina P Farrell, Idan Gabdank, Yoel Gofin, David U Gorkin, Mengting Gu, Vivian Hecht, Benjamin C Hitz, Robbyn Issner, Melanie Kirsche, Xiangmeng Kong, Bonita R Lam, Shantao Li, Bian Li, Tianxiao Li, Xiqi Li, Khine Zin Lin, Ruibang Luo, Mark Mackiewicz, Jill E Moore, Jonathan Mudge, Nicholas Nelson, Chad Nusbaum, Ioann Popov, Henry E Pratt, Yunjiang Qiu, Srividya Ramakrishnan, Joe Raymond, Leonidas Salichos, Alexandra Scavelli, Jacob M Schreiber, Fritz J Sedlazeck, Lei Hoon See, Rachel M Sherman, Xu Shi, Minyi Shi, Cricket Alicia Sloan, J Seth Strattan, Zhen Tan, Forrest Y Tanaka, Anna Vlasova, Jun Wang, Jonathan Werner, Brian Williams, Min Xu, Chengfei Yan, Lu Yu, Christopher Zaleski, Jing Zhang, J Michael Cherry, Eric M Mendenhall, William S Noble, Zhiping Weng, Morgan E Levine, Alexander Dobin, Barbara Wold, Ali Mortazavi, Bing Ren, Jesse Gillis, Richard M Myers, Michael P Snyder, Jyoti Choudhary, Aleksandar Milosavljevic, Michael C Schatz, Roderic Guigó, Bradley E Bernstein, Thomas R Gingeras, Mark Gerstein
doi: https://doi.org/10.1101/2021.04.26.441442
Joel Rozowsky
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Jorg Drenkow
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Yucheng T Yang
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Gamze Gursoy
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Timur Galeev
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Beatrice Borsari
4Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain
Charles B Epstein
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Kun Xiong
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Jinrui Xu
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Jiahao Gao
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Keyang Yu
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Ana Berthel
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Zhanlin Chen
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Fabio Navarro
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Jason Liu
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Maxwell S Sun
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
James Wright
7Institute of Cancer Research, London, UK
Justin Chang
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Christopher JF Cameron
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Noam Shoresh
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Elizabeth Gaskell
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jessika Adrian
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Sergey Aganezov
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
Gabriela Balderrama-Gutierrez
10Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
Samridhi Banskota
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Guillermo Barreto Corona
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Sora Chee
11Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA
Surya B Chhetri
12Biological Sciences, University of Alabama in Huntsville, Huntsville, AL, USA
Gabriel Conte Cortez Martins
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Cassidy Danyko
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Carrie A Davis
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Daniel Farid
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Nina P Farrell
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Idan Gabdank
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Yoel Gofin
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
David U Gorkin
11Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA
Mengting Gu
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Vivian Hecht
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Benjamin C Hitz
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Robbyn Issner
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Melanie Kirsche
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
Xiangmeng Kong
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Bonita R Lam
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Shantao Li
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Bian Li
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Tianxiao Li
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Xiqi Li
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Khine Zin Lin
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Ruibang Luo
13Department of Computer Science, The University of Hong Kong, Hong Kong, CHN
Mark Mackiewicz
14HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Jill E Moore
15Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA
Jonathan Mudge
16European Bioinformatics Institute, Cambridge, Cambridgeshire, GB
Nicholas Nelson
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Chad Nusbaum
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Ioann Popov
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Henry E Pratt
15Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA
Yunjiang Qiu
11Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA
Srividya Ramakrishnan
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
Joe Raymond
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
Leonidas Salichos
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
17Department of Biological and Chemical Sciences, New York Institute of Technology, Old Westbury, NY, USA
Alexandra Scavelli
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Jacob M Schreiber
18Department of Genome Sciences, University of Washington, Seattle, WA, USA
Fritz J Sedlazeck
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
19Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
20Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Lei Hoon See
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Rachel M Sherman
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
Xu Shi
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Minyi Shi
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Cricket Alicia Sloan
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
J Seth Strattan
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Zhen Tan
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Forrest Y Tanaka
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Anna Vlasova
4Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain
21Comparative Genomics Group, Life Science Programme, Barcelona Supercomputing Centre, Barcelona, Spain
22Institute of Research in Biomedicine, Barcelona, Spain
Jun Wang
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Jonathan Werner
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Brian Williams
23Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
Min Xu
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Chengfei Yan
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Lu Yu
7Institute of Cancer Research, London, UK
Christopher Zaleski
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Jing Zhang
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
24Department of Computer Science, University of California, Irvine, CA, USA
J Michael Cherry
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Eric M Mendenhall
12Biological Sciences, University of Alabama in Huntsville, Huntsville, AL, USA
William S Noble
18Department of Genome Sciences, University of Washington, Seattle, WA, USA
Zhiping Weng
15Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA, USA
Morgan E Levine
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
25Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
Alexander Dobin
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Barbara Wold
23Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
Ali Mortazavi
10Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
Bing Ren
11Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA, USA
Jesse Gillis
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Richard M Myers
14HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
Michael P Snyder
8Department of Genetics, School of Medicine, Stanford University, Palo Alto, CA, USA
Jyoti Choudhary
7Institute of Cancer Research, London, UK
Aleksandar Milosavljevic
6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Michael C Schatz
9Departments of Computer Science and Biology, Johns Hopkins University, Baltimore, MD, USA
19Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Roderic Guigó
4Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain
26Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
Bradley E Bernstein
5Broad Institute of MIT and Harvard, Cambridge, MA, USA
27Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Thomas R Gingeras
3Functional Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
Mark Gerstein
1Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
2Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
Abstract
Evaluating the impact of genetic variants on transcriptional regulation is a central goal in biological science that has been constrained by reliance on a single reference genome. To address this, we constructed phased, diploid genomes for four cadaveric donors (using long-read sequencing) and systematically charted noncoding regulatory elements and transcriptional activity across more than 25 tissues from these donors. Integrative analysis revealed over a million variants with allele-specific activity, coordinated, locus-scale allelic imbalances, and structural variants impacting proximal chromatin structure. We relate the personal genome analysis to the ENCODE encyclopedia, annotating allele- and tissue-specific elements that are strongly enriched for variants impacting expression and disease phenotypes. These experimental and statistical approaches, and the corresponding EN-TEx resource, provide a framework for personalized functional genomics.
Competing Interest Statement
The authors have declared no competing interest.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted April 26, 2021.
Multi-tissue integrative analysis of personal epigenomes
Joel Rozowsky, Jorg Drenkow, Yucheng T Yang, Gamze Gursoy, Timur Galeev, Beatrice Borsari, Charles B Epstein, Kun Xiong, Jinrui Xu, Jiahao Gao, Keyang Yu, Ana Berthel, Zhanlin Chen, Fabio Navarro, Jason Liu, Maxwell S Sun, James Wright, Justin Chang, Christopher JF Cameron, Noam Shoresh, Elizabeth Gaskell, Jessika Adrian, Sergey Aganezov, Gabriela Balderrama-Gutierrez, Samridhi Banskota, Guillermo Barreto Corona, Sora Chee, Surya B Chhetri, Gabriel Conte Cortez Martins, Cassidy Danyko, Carrie A Davis, Daniel Farid, Nina P Farrell, Idan Gabdank, Yoel Gofin, David U Gorkin, Mengting Gu, Vivian Hecht, Benjamin C Hitz, Robbyn Issner, Melanie Kirsche, Xiangmeng Kong, Bonita R Lam, Shantao Li, Bian Li, Tianxiao Li, Xiqi Li, Khine Zin Lin, Ruibang Luo, Mark Mackiewicz, Jill E Moore, Jonathan Mudge, Nicholas Nelson, Chad Nusbaum, Ioann Popov, Henry E Pratt, Yunjiang Qiu, Srividya Ramakrishnan, Joe Raymond, Leonidas Salichos, Alexandra Scavelli, Jacob M Schreiber, Fritz J Sedlazeck, Lei Hoon See, Rachel M Sherman, Xu Shi, Minyi Shi, Cricket Alicia Sloan, J Seth Strattan, Zhen Tan, Forrest Y Tanaka, Anna Vlasova, Jun Wang, Jonathan Werner, Brian Williams, Min Xu, Chengfei Yan, Lu Yu, Christopher Zaleski, Jing Zhang, J Michael Cherry, Eric M Mendenhall, William S Noble, Zhiping Weng, Morgan E Levine, Alexander Dobin, Barbara Wold, Ali Mortazavi, Bing Ren, Jesse Gillis, Richard M Myers, Michael P Snyder, Jyoti Choudhary, Aleksandar Milosavljevic, Michael C Schatz, Roderic Guigó, Bradley E Bernstein, Thomas R Gingeras, Mark Gerstein
bioRxiv 2021.04.26.441442; doi: https://doi.org/10.1101/2021.04.26.441442
Multi-tissue integrative analysis of personal epigenomes
Joel Rozowsky, Jorg Drenkow, Yucheng T Yang, Gamze Gursoy, Timur Galeev, Beatrice Borsari, Charles B Epstein, Kun Xiong, Jinrui Xu, Jiahao Gao, Keyang Yu, Ana Berthel, Zhanlin Chen, Fabio Navarro, Jason Liu, Maxwell S Sun, James Wright, Justin Chang, Christopher JF Cameron, Noam Shoresh, Elizabeth Gaskell, Jessika Adrian, Sergey Aganezov, Gabriela Balderrama-Gutierrez, Samridhi Banskota, Guillermo Barreto Corona, Sora Chee, Surya B Chhetri, Gabriel Conte Cortez Martins, Cassidy Danyko, Carrie A Davis, Daniel Farid, Nina P Farrell, Idan Gabdank, Yoel Gofin, David U Gorkin, Mengting Gu, Vivian Hecht, Benjamin C Hitz, Robbyn Issner, Melanie Kirsche, Xiangmeng Kong, Bonita R Lam, Shantao Li, Bian Li, Tianxiao Li, Xiqi Li, Khine Zin Lin, Ruibang Luo, Mark Mackiewicz, Jill E Moore, Jonathan Mudge, Nicholas Nelson, Chad Nusbaum, Ioann Popov, Henry E Pratt, Yunjiang Qiu, Srividya Ramakrishnan, Joe Raymond, Leonidas Salichos, Alexandra Scavelli, Jacob M Schreiber, Fritz J Sedlazeck, Lei Hoon See, Rachel M Sherman, Xu Shi, Minyi Shi, Cricket Alicia Sloan, J Seth Strattan, Zhen Tan, Forrest Y Tanaka, Anna Vlasova, Jun Wang, Jonathan Werner, Brian Williams, Min Xu, Chengfei Yan, Lu Yu, Christopher Zaleski, Jing Zhang, J Michael Cherry, Eric M Mendenhall, William S Noble, Zhiping Weng, Morgan E Levine, Alexander Dobin, Barbara Wold, Ali Mortazavi, Bing Ren, Jesse Gillis, Richard M Myers, Michael P Snyder, Jyoti Choudhary, Aleksandar Milosavljevic, Michael C Schatz, Roderic Guigó, Bradley E Bernstein, Thomas R Gingeras, Mark Gerstein
bioRxiv 2021.04.26.441442; doi: https://doi.org/10.1101/2021.04.26.441442
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