A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortium’s (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.
HPRC2: A human pangenome reference with near-complete coverage of common genetic variation
Julian K. Lucas, Prajna Hebbar, Wen-Wei Liao, Juan F. Macias-Velasco, Adam M. Novak, Mobin Asri, Jennifer R. Balacco, Andrew P. Blair, Jana Ebler, Joshua M.V. Gardner, Margarita Geleta, Cristian Groza, Andrea Guarracino, Peter Heringer, Glenn Hickey, Shuangjia Lu, Maximillian G. Marin, Christopher Markovic, Mira Mastoras, Capucine Mayoud, Brandy McNulty, Julian M. Menendez, Anna Minkina, Saswat K. Mohanty, Jean Monlong, Katherine M. Munson, Keisuke K. Oshima, David Porubsky, T. Rhyker Ranallo-Benavidez, William E. Seligmann, Ruhollah Shemirani, Ivo Violich, DongAhn Yoo, Xiaoyu Zhuo, Derek Albracht, Ivan A. Alexandrov, Jamie Allen, Alawi A. Alsheikh-Ali, Casey Andrews, Dmitry Antipov, Lucinda Antonacci-Fulton, Alexander Arguello, Marcelo Ayllon, Edward A. Belter, Halle D. Bender, Davide Bolognini, Katherine E. Bonini, Silvia Buonaiuto, Shuo Cao, Ann M. Mc Cartney, Pi-Chuan Chang, Xian Chang, Jitender Cheema, Claudio Ciofi, Hiram Clawson, Sarah Cody, Vincenza Colonna, Holland C. Conwell, Mark Diekhans, Maria Angela Diroma, Zheng Dong, Danilo Dubocanin, Jordan M. Eizenga, Parsa Eskandar, Eddie Ferro, Sarah M. Ford, Willard W. Ford, Adam Frankish, Mallory A. Freeberg, Qichen Fu, Shenghan Gao, Yan Gao, Gage H. Garcia, Obed A. Garcia, John E. Garza, Mohammadmersad Ghorbani, Tina A. Graves-Lindsay, Bida Gu, Leanne Haggerty, Nancy F. Hansen, Yue Hao, Todd L. Hillaker, S. Nakib Hossain, Neng Huang, Sarah E. Hunt, Toby Hunt, Nafiseh Jafarzadeh, Nivesh Jain, Maryam Jehangir, Juan Jiang, Juhyun Kim, Bonhwang Koo, Milinn Kremitzki, Daofeng Li, Ronghan Li, Jiadong Lin, Tianjie Liu, Ryan Lorig-Roach, Hailey Loucks, Jane E. Loveland, Jianguo Lu, Walfred Ma, Franco L. Marsico, Jack A. Medico, Younes Mokrab, Shabir Moosa, Avelina Moreno-Ochando, Shinichi Morishita, Jonathan M. Mudge, Njagi Mwaniki, Nasna Nassir, Chiara Natali, Shloka Negi, Lingbin Ni, Faith Okamoto, Chie Owa, Sadye Paez, Clelia Peano, Brandon D. Pickett, Laura Pignata, Timofey Prodanov, Anandi Radhakrishnan, Brian J. Raney, Alessandro Raveane, Andreas Rechtsteiner, Luyao Ren, Arang Rhie, Fedor Ryabov, Samuel Sacco, Farnaz Salehi, Aarushi Sehgal, Mahsa Shabani, Shadi Shahatit, Vikram S. Shivakumar, Swati Sinha, Linnea Smeds, Steven J. Solar, Marco Sollitto, Nicole Soranzo, Marie-Marthe Suner, Yoshihiko Suzuki, Arda Soylev, Jack A.S. Tierney, Chad Tomlinson, Francesca Floriana Tricomi, Matteo Tommaso Ungaro, Rahul Varki, Brian P. Walenz, Charles Wang, Lisa E. Wang, Aaron M. Wenger, Conor V. Whelan, Zilan Xin, Zheng Xu, Wenjin Zhang, Ying Zhou, Giulia Zunino, Nicolas Altemose, Floris P. Barthel, Christina Boucher, Guillaume Bourque, Andrew Carroll, Monika Cechova, Mark J.P. Chaisson, Haoyu Cheng, Robert Cook-Deegan, Daniel Doerr, Richard Durbin, Anna-Sophie Fiston-Lavier, Giulio Formenti, Stephanie M. Fullerton, Robert S. Fulton, Shilpa Garg, Nanibaa' A. Garrison, Richard E. Green, Carol W. Greider, Melissa Gymrek, Maximilian Haeussler, Mohammad Amiruddin Hashmi, David Haussler, Alexander G. Ioannidis, Sergey Koren, Charles H. Langley, Ben Langmead, Heather A. Lawson, Glennis A. Logsdon, Kateryna D. Makova, Fergal J. Martin, Matthew W. Mitchell, Pilar N. Ossorio, Nadia Pisanti, Pjotr Prins, Mikko Rautiainen, Michael C. Schatz, Laura B. Scheinfeldt, Kishwar Shafin, Jouni Siren, Andrew B. Stergachis, Ahmad Abou Tayoun, Mohammed Uddin, Flavia Villani, Mitchell R. Vollger, Kai Ye, Evan E. Eichler, Erik Garrison, Ira M. Hall, Erich D. Jarvis, Eimear E. Kenny, Heng Li, Jonathan LoTempio, Tobias Marschall, Karen H. Miga, Adam M. Phillippy, Ting Wang, Benedict Paten
2026.
bioRxiv. 2026