HPRC2: A human pangenome reference with near-complete coverage of common genetic variation
Jul 22, 2026·
JK Lucas, P Hebbar, W-W Liao, JF Macias-Velasco, AM Novak, M Asri, JR Balacco, AP Blair, D Bolognini, J Ebler, JMV Gardner, M Geleta, C Groza, A Guarracino, P Heringer, G Hickey, S Koren, S Lu, MG Marin, C Markovic, M Mastoras, C Mayoud, B McNulty, JM Menendez, A Minkina, SK Mohanty, J Monlong, KM Munson, KK Oshima, D Porubsky, TR Ranallo-Benavidez, A Raveane, WE Seligmann, R Shemirani, Y Suzuki, JAS Tierney, I Violich, D Yoo, X Zhuo, D Albracht, IA Alexandrov, J Allen, AA Alsheikh-Ali, C Andrews, D Antipov, L Antonacci-Fulton, A Arguello, MAyllon, EA Belter Jr, HD Bender, KE Bonini, S Buonaiuto, S Cao, AM Mc Cartney, P-C Chang, X Chang, J Cheema, C Ciofi, H Clawson, S Cody, V Colonna, HC Conwell, M Diekhans, MA Diroma, Z Dong, D Dubocanin, JM Eizenga, P Eskandar, E Ferro, SM Ford, WW Ford, A Frankish, MA Freeberg, Q Fu, S Gao, Y Gao, GH Garcia, OA Garcia, JE Garza, M Ghorbani, TA Graves-Lindsay, B Gu, L Haggerty, NF Hansen, Y Hao, TL Hillaker, SN Hossain, N Huang, SE Hunt, T Hunt, N Jafarzadeh, N Jain, M Jehangir, J Jiang, J Kim, B Koo, M Kremitzki, D Li, R Li, J Lin, T Liu, R Lorig-Roach, H Loucks, JE Loveland, J Lu, W Ma, FL Marsico, JA Medico, Y Mokrab, S Moosa, A Moreno-Ochando, S Morishita, JM Mudge, N Mwaniki, N Nassir, C Natali, S Negi, L Ni, F Okamoto, C Owa, S Paez, C Peano, BD Pickett, L Pignata, T Prodanov, A Radhakrishnan, BJ Raney, A Rechtsteiner, L Ren, F Ryabov, S Sacco, F Salehi, A Sehgal, M Shabani, M Shahatit, VS Shivakumar, S Sinha, L Smeds, SJ Solar, S Sollitto, N Soranzo, M-M Suner, A Söylev, C Tomlinson, FF Tricomi, MT Ungaro, R Varki, BP Walenz, C Wang, LE Wang, AM Wenger, CV Whelan, Z Xin, Z Xu, W Zhang, Y Zhou, G Zunino, N Altemose, FP Barthel, C Boucher, G Bourque, A Carroll, M Cechova, MJP Chaisson, H Cheng, R Cook-Deegan, D Doerr, R Durbin, A-S Fiston-Lavier, G Formenti, SM Fullerton, RS Fulton, S Garg, NA Garrison, RE Green, CW Greider, M Gymrek, M Haeussler, MA Hashmi, D Haussler, AG Ioannidis, CH Langley, B Langmead, HA Lawson, GA Logsdon, KD Makova, FJ Martin, MW Mitchell, PN Ossorio, N Pisanti, P Prins, M Rautiainen, A Rhie, MC Schatz, LB Scheinfeldt, K Shafin, J Sirén, AB Stergachis, AA Tayoun, M Uddin, F Villani, MR Vollger, K Ye, EE Eichler, E Garrison, IM Hall, ED Jarvis, EE Kenny, H Li, J LoTempio Jr, T Marschall, KH Miga, AM Phillippy, T Wang, B Paten
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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.
Type
Publication
bioRxiv
Authors
Ph.D. Student
Saswat is interested in understanding the evolution of non-B-DNA structures in primates. Currently, he is working mainly on a specific type of non-B-DNA structure called the G-quadruplex or G4, for example, developing bioinformatic tools to analyze genome-wide distribution of these structures.
Authors
Postdoctoral Scholar
Linnéa’s research in the Makova lab involves investigating selection in non-canonical DNA from primates, especially G4 quadruplexes, using bioinformatics methods. Linnéa worked for 8 years as a bioinformatician in Dr. Hans Ellegren’s lab, developing approaches to study speciation, mutation rate and sex chromosome evolution in birds, before taking on a Ph. D. in evolutionary genetics. Her thesis “Conservation genomics in inbred Scandinavian wolves using bioinformatic methods” involved work on Y chromosome evolution, admixture, genetic load and structural variation.
Authors
Ph.D. student
I enjoy bioinformatics as a tool to study evolution of sex chromosomes,
transposable elements and gene expression. I am interested in
topics covering RNASeq, variant calling, mapping, genome assembly
and new sequencing technologies.
Authors
Professor
Kateryna is interested in genomics, evolution, and human genetics.
Her lab studies mutations using both computational and experimental
approaches. Additional topics of interest include sex chromosome
evolution and genomics of childhood obesity.
Authors
Dr. Adam Phillippy is a Senior Investigator and head of the Genome Informatics Section at the National Human Genome Research Institute. His lab develops and applies computational methods for the analysis of massive genomics datasets, focusing on the challenges of genome sequencing and comparative genomics. He is a pioneer of single-molecule sequencing for the reconstruction of complete genomes and is best known for his work on completing the human genome from “telomere to telomere”.