PreprintCC BYbioRxiv (Cold Spring Harbor Laboratory)
HPRC2: A human pangenome reference with near-complete coverage of common genetic variation
29 affiliations
- 1UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA 95060, USA;
- 2Center for Genomic Health, Yale University School of Medicine, New Haven, CT 06510, USA;
- 3McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA;
- 4The Vertebrate Genome Laboratory, The Rockefeller University, New York, NY 10065, USA;
- 5Center for Digital Medicine, Heinrich Heine University Dusseldorf, Dusseldorf, NRW, DE;
- 6Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA;
- 7Montreal Heart Institute, Montreal, QC, Canada;
- 8Bioinnovation and Genome Sciences, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA;
- 9Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA;
- 10ISEM, Univ Montpellier, CNRS, IRD, Montpellier, FR;
- 11Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA;
- 12Department of Biology, Penn State University, University Park, PA 16802, USA;
- 13IRSD - Digestive Health Research Institute, University of Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, FR;
- 14Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA;
- 15Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
- 16Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, CA 95060, USA;
- 17Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- 18Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA;
- 19Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel;
- 20None;
- 21Center for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai, UAE;
- 22Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA;
- 23Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD 20871 USA;
- 24Human Technopole, Milan, Italy;
- 25Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
- 26Institute of Clinical and Translational Sciences, University of California, Irvine, CA 92697, USA;
- 27Google LLC, Mountain View, CA 94043, USA;
- 28European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK;
- 29Department of Biology, University of Florence, Sesto Fiorentino, FI 50019, Italy;
Abstract
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.
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BibTeX
@misc{lucas2026hprc2,
title = {{HPRC2: A human pangenome reference with near-complete coverage of common genetic variation}},
author = {Julian Lucas and Prajna Hebbar and Wen‐Wei Liao and Juan F Macias-Velasco and Adam M. Novak and Mobin Asri and Jennifer Balacco and Andrew P. Blair and Jana Ebler and Joshua M.V. Gardner and Margarita Geleta and Cristian Groza and Andrea Guarracino and Peter Heringer and Glenn Hickey and Shuangjia Lu and Maximillian G. Marin and Christopher Markovic and Mira Mastoras and Capucine Mayoud and Brandy McNulty and Julian M. Menendez and Anna Minkina and Saswat K. Mohanty and Jean Monlong and Katherine M. Munson and Keisuke K. Oshima and David Porubskỳ and T. Rhyker Ranallo-Benavidez and William Seligmann and Ruhollah Shemirani and Ivo Violich and DongAhn Yoo and Xiaoyu Zhuo and Derek Albracht and Ivan A. Alexandrov and Jamie Allen and Alawi A.A. Alsheikh-Ali and Casey Andrews and Dmitry Antipov and Lucinda L. Antonacci-Fulton and Alexander Arguello and Marcelo Ayllon and Edward A. Belter and Halle D. Bender and Davide Bolognini and Katherine E. Bonini and Silvia Buonaiuto and Shuo Cao and Ann M. Mc Cartney and Pi-Chuan Chang and Xian H. Chang and Jitender Cheema and Claúdio Ciofi and Hiram Clawson and Sarah Cody and Vincenza Colonna and Holland C. Conwell and Mark Diekhans and Maria Angela Diroma},
howpublished = {bioRxiv (Cold Spring Harbor Laboratory)},
year = {2026},
month = jul,
doi = {10.64898/2026.07.21.739710},
url = {https://doi.org/10.64898/2026.07.21.739710},
note = {CC BY},
}
RIS
TY - UNPB
TI - HPRC2: A human pangenome reference with near-complete coverage of common genetic variation
AU - Julian Lucas
AU - Prajna Hebbar
AU - Wen‐Wei Liao
AU - Juan F Macias-Velasco
AU - Adam M. Novak
AU - Mobin Asri
AU - Jennifer Balacco
AU - Andrew P. Blair
AU - Jana Ebler
AU - Joshua M.V. Gardner
AU - Margarita Geleta
AU - Cristian Groza
AU - Andrea Guarracino
AU - Peter Heringer
AU - Glenn Hickey
AU - Shuangjia Lu
AU - Maximillian G. Marin
AU - Christopher Markovic
AU - Mira Mastoras
AU - Capucine Mayoud
AU - Brandy McNulty
AU - Julian M. Menendez
AU - Anna Minkina
AU - Saswat K. Mohanty
AU - Jean Monlong
AU - Katherine M. Munson
AU - Keisuke K. Oshima
AU - David Porubskỳ
AU - T. Rhyker Ranallo-Benavidez
AU - William Seligmann
AU - Ruhollah Shemirani
AU - Ivo Violich
AU - DongAhn Yoo
AU - Xiaoyu Zhuo
AU - Derek Albracht
AU - Ivan A. Alexandrov
AU - Jamie Allen
AU - Alawi A.A. Alsheikh-Ali
AU - Casey Andrews
AU - Dmitry Antipov
AU - Lucinda L. Antonacci-Fulton
AU - Alexander Arguello
AU - Marcelo Ayllon
AU - Edward A. Belter
AU - Halle D. Bender
AU - Davide Bolognini
AU - Katherine E. Bonini
AU - Silvia Buonaiuto
AU - Shuo Cao
AU - Ann M. Mc Cartney
AU - Pi-Chuan Chang
AU - Xian H. Chang
AU - Jitender Cheema
AU - Claúdio Ciofi
AU - Hiram Clawson
AU - Sarah Cody
AU - Vincenza Colonna
AU - Holland C. Conwell
AU - Mark Diekhans
AU - Maria Angela Diroma
PY - 2026
DA - 2026/07/22
PB - bioRxiv (Cold Spring Harbor Laboratory)
DO - 10.64898/2026.07.21.739710
UR - https://doi.org/10.64898/2026.07.21.739710
AB - 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.
ER -