{ "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.", "abstract_shown": true, "affiliations": [ "UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA 95060, USA;", "Center for Genomic Health, Yale University School of Medicine, New Haven, CT 06510, USA;", "McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, USA;", "The Vertebrate Genome Laboratory, The Rockefeller University, New York, NY 10065, USA;", "Center for Digital Medicine, Heinrich Heine University Dusseldorf, Dusseldorf, NRW, DE;", "Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA;", "Montreal Heart Institute, Montreal, QC, Canada;", "Bioinnovation and Genome Sciences, The Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA;", "Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA;", "ISEM, Univ Montpellier, CNRS, IRD, Montpellier, FR;", "Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA;", "Department of Biology, Penn State University, University Park, PA 16802, USA;", "IRSD - Digestive Health Research Institute, University of Toulouse, INSERM, INRAE, ENVT, UPS, Toulouse, FR;", "Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA;", "Department of Genetics, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;", "Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, CA 95060, USA;", "Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;", "Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA;", "Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel;", "None;", "Center for Applied and Translational Genomics (CATG), Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai, UAE;", "Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA;", "Division of Genome Sciences, National Human Genome Research Institute, Bethesda, MD 20871 USA;", "Human Technopole, Milan, Italy;", "Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA;", "Institute of Clinical and Translational Sciences, University of California, Irvine, CA 92697, USA;", "Google LLC, Mountain View, CA 94043, USA;", "European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK;", "Department of Biology, University of Florence, Sesto Fiorentino, FI 50019, Italy;" ], "article_type": null, "arxiv": null, "author_total": 100, "authors": [ { "affs": [ 0 ], "name": "Julian Lucas", "orcid": "0000-0001-9163-2756" }, { "affs": [ 0 ], "name": "Prajna Hebbar", "orcid": "0009-0008-9817-5330" }, { "affs": [ 1 ], "name": "Wen‐Wei Liao", "orcid": "0000-0001-8183-213X" }, { "affs": [ 2 ], "name": "Juan F Macias-Velasco", "orcid": "0000-0003-2827-4647" }, { "affs": [ 0 ], "name": "Adam M. Novak", "orcid": "0000-0001-5828-047X" }, { "affs": [ 0 ], "name": "Mobin Asri", "orcid": "0000-0002-7194-5138" }, { "affs": [ 3 ], "name": "Jennifer Balacco", "orcid": "0000-0001-7102-1632" }, { "affs": [ 0 ], "name": "Andrew P. Blair", "orcid": "0000-0002-3196-6233" }, { "affs": [ 4 ], "name": "Jana Ebler", "orcid": "0000-0002-0382-3702" }, { "affs": [ 0 ], "name": "Joshua M.V. Gardner", "orcid": "0000-0003-4386-0628" }, { "affs": [ 5 ], "name": "Margarita Geleta", "orcid": "0000-0001-5823-9776" }, { "affs": [ 6 ], "name": "Cristian Groza", "orcid": "0000-0001-6624-5404" }, { "affs": [ 7 ], "name": "Andrea Guarracino", "orcid": "0000-0001-9744-131X" }, { "affs": [ 4 ], "name": "Peter Heringer", "orcid": "0009-0005-5985-2317" }, { "affs": [ 0 ], "name": "Glenn Hickey", "orcid": "0000-0002-2280-9404" }, { "affs": [ 1 ], "name": "Shuangjia Lu", "orcid": "0000-0001-8571-6902" }, { "affs": [ 8 ], "name": "Maximillian G. Marin", "orcid": "0000-0002-9108-3328" }, { "affs": [ 2 ], "name": "Christopher Markovic" }, { "affs": [ 0 ], "name": "Mira Mastoras", "orcid": "0000-0001-6897-0116" }, { "affs": [ 9 ], "name": "Capucine Mayoud" }, { "affs": [ 0 ], "name": "Brandy McNulty" }, { "affs": [ 0 ], "name": "Julian M. Menendez", "orcid": "0000-0002-0002-8543" }, { "affs": [ 10 ], "name": "Anna Minkina", "orcid": "0000-0002-7989-4478" }, { "affs": [ 11 ], "name": "Saswat K. Mohanty", "orcid": "0000-0002-1813-589X" }, { "affs": [ 12 ], "name": "Jean Monlong", "orcid": "0000-0002-9737-5516" }, { "affs": [ 13 ], "name": "Katherine M. Munson", "orcid": "0000-0001-8413-6498" }, { "affs": [ 14 ], "name": "Keisuke K. Oshima", "orcid": "0009-0002-2229-8998" }, { "affs": [ 13 ], "name": "David Porubskỳ", "orcid": "0000-0001-8414-8966" }, { "affs": [ 7 ], "name": "T. Rhyker Ranallo-Benavidez", "orcid": "0000-0003-3137-8439" }, { "affs": [ 15 ], "name": "William Seligmann", "orcid": "0000-0002-5762-3095" }, { "affs": [ 16 ], "name": "Ruhollah Shemirani", "orcid": "0000-0003-1065-7244" }, { "affs": [ 0 ], "name": "Ivo Violich" }, { "affs": [ 13 ], "name": "DongAhn Yoo", "orcid": "0000-0003-0033-3721" }, { "affs": [ 17 ], "name": "Xiaoyu Zhuo", "orcid": "0000-0002-1400-5609" }, { "affs": [ 2 ], "name": "Derek Albracht" }, { "affs": [ 18 ], "name": "Ivan A. Alexandrov", "orcid": "0000-0003-4342-2003" }, { "affs": [ 19 ], "name": "Jamie Allen" }, { "affs": [ 20 ], "name": "Alawi A.A. Alsheikh-Ali", "orcid": "0000-0002-1213-4546" }, { "affs": [ 17 ], "name": "Casey Andrews" }, { "affs": [ 21 ], "name": "Dmitry Antipov", "orcid": "0000-0002-6087-0660" }, { "affs": [ 2 ], "name": "Lucinda L. Antonacci-Fulton" }, { "affs": [ 22 ], "name": "Alexander Arguello" }, { "affs": [ 13 ], "name": "Marcelo Ayllon", "orcid": "0000-0003-0360-5446" }, { "affs": [ 2 ], "name": "Edward A. Belter", "orcid": "0009-0009-9083-8918" }, { "affs": [ 0 ], "name": "Halle D. Bender" }, { "affs": [ 23 ], "name": "Davide Bolognini", "orcid": "0000-0002-8735-8093" }, { "affs": [ 16 ], "name": "Katherine E. Bonini", "orcid": "0000-0001-7721-8137" }, { "affs": [ 24 ], "name": "Silvia Buonaiuto", "orcid": "0000-0002-7423-7110" }, { "affs": [ 24 ], "name": "Shuo Cao", "orcid": "0009-0006-5754-7332" }, { "affs": [ 25 ], "name": "Ann M. Mc Cartney", "orcid": "0000-0001-5853-3772" }, { "affs": [ 26 ], "name": "Pi-Chuan Chang", "orcid": "0000-0003-3021-6446" }, { "affs": [ 0 ], "name": "Xian H. Chang", "orcid": "0000-0002-3801-4542" }, { "affs": [ 27 ], "name": "Jitender Cheema", "orcid": "0009-0007-7505-2592" }, { "affs": [ 28 ], "name": "Claúdio Ciofi", "orcid": "0000-0001-8537-8659" }, { "affs": [ 0 ], "name": "Hiram Clawson", "orcid": "0000-0002-0480-0545" }, { "affs": [ 2 ], "name": "Sarah Cody" }, { "affs": [ 24 ], "name": "Vincenza Colonna", "orcid": "0000-0002-3966-0474" }, { "affs": [ 15 ], "name": "Holland C. Conwell", "orcid": "0009-0005-2362-2966" }, { "affs": [ 0 ], "name": "Mark Diekhans", "orcid": "0000-0002-0430-0989" }, { "affs": [ 28 ], "name": "Maria Angela Diroma", "orcid": "0000-0003-1427-8946" } ], "bibtex": "https://research.draconitic.com/paper/748ddsa0rzye9.bib", "cited_by": 21, "doi": "10.64898/2026.07.21.739710", "fulltext_url": null, "id": "748ddsa0rzye9", "issns": [], "landing_url": "https://doi.org/10.64898/2026.07.21.739710", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1312|Genomics and Phylogenetic Studies" ] ], "openalex": "W7170083314", "pdf_url": null, "pmcid": "PMC13419748", "pmid": "42539208", "published": "2026-07-22", "publisher": "Cold Spring Harbor Laboratory", "ris": "https://research.draconitic.com/paper/748ddsa0rzye9.ris", "sources": [ { "first_seen": "2026-10-30T13:26:46Z", "native_id": "W7170083314", "source": "openalex", "url": "https://doi.org/10.64898/2026.07.21.739710" } ], "subjects": [ { "field": "biochemistry", "origin": "openalex:1312|Genomics and Phylogenetic Studies", "subfield": "molecular-biology" } ], "title": "HPRC2: A human pangenome reference with near-complete coverage of common genetic variation", "title_text": "HPRC2: A human pangenome reference with near-complete coverage of common genetic variation", "type": "preprint", "updated_at": "2026-11-07T13:20:47Z", "url": "https://research.draconitic.com/paper/748ddsa0rzye9", "venue": "bioRxiv (Cold Spring Harbor Laboratory)", "versions": [] }