Multi-tissue integrative analysis of personal epigenomes

Rozowsky, Joel; Drenkow, Jorg; Yang, Yucheng T; Gursoy, Gamze; Galeev, Timur; Borsari, Beatrice; Epstein, Charles B; Xiong, Kun; Xu, Jinrui; Gao, Jiahao; Yu, Keyang; Berthel, Ana; Chen, Zhanlin; Navarro, Fabio; Liu, Jason; Sun, Maxwell S; Wright, James; Chang, Justin; Cameron, Christopher JF; Shoresh, Noam; Gaskell, Elizabeth; Adrian, Jessika; Aganezov, Sergey; Balderrama-Gutierrez, Gabriela; Banskota, Samridhi; Corona, Guillermo Barreto; Chee, Sora; Chhetri, Surya B; Cortez Martins, Gabriel Conte; Danyko, Cassidy; Davis, Carrie A; Farid, Daniel; Farrell, Nina P; Gabdank, Idan; Gofin, Yoel; Gorkin, David U; Gu, Mengting; Hecht, Vivian; Hitz, Benjamin C; Issner, Robbyn; Kirsche, Melanie; Kong, Xiangmeng; Lam, Bonita R; Li, Shantao; Li, Bian; Li, Tianxiao; Li, Xiqi; Lin, Khine Zin; Luo, Ruibang; Mackiewicz, Mark; Moore, Jill E; Mudge, Jonathan; Nelson, Nicholas; Nusbaum, Chad; Popov, Ioann; Pratt, Henry E; Qiu, Yunjiang; Ramakrishnan, Srividya; Raymond, Joe; Salichos, Leonidas; Scavelli, Alexandra; Schreiber, Jacob M; Sedlazeck, Fritz J; See, Lei Hoon; Sherman, Rachel M; Shi, Xu; Shi, Minyi; Sloan, Cricket Alicia; Strattan, J Seth; Tan, Zhen; Tanaka, Forrest Y; Vlasova, Anna; Wang, Jun; Werner, Jonathan; Williams, Brian; Xu, Min; Yan, Chengfei; Yu, Lu; Zaleski, Christopher; Zhang, Jing; Cherry, J Michael; Mendenhall, Eric M; Noble, William S; Weng, Zhiping; Levine, Morgan E; Dobin, Alexander; Wold, Barbara; Mortazavi, Ali; Ren, Bing; Gillis, Jesse; Myers, Richard M; Snyder, Michael P; Choudhary, Jyoti; Milosavljevic, Aleksandar; Schatz, Michael C; Guigó, Roderic; Bernstein, Bradley E; Gingeras, Thomas R; Gerstein, Mark

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.