Loh, Po-RuDanecek, PetrPalamara, Pier FrancescoFuchsberger, ChristianReshef, YakirFinucane, HilarySchoenherr, SebastianForer, LukasMcCarthy, ShaneAbecasis, Goncalo RDurbin, RichardPrice, Alkes2017-05-012016Loh, P., P. Danecek, P. F. Palamara, C. Fuchsberger, Y. A. Reshef, H. K. Finucane, S. Schoenherr, et al. 2016. “Reference-based phasing using the Haplotype Reference Consortium panel.” Nature genetics 48 (11): 1443-1448. doi:10.1038/ng.3679. http://dx.doi.org/10.1038/ng.3679.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630668Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing within a genotyped cohort, an approach that can attain high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here, we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium, HRC) using a new data structure based on the positional Burrows-Wheeler transform. We demonstrate that Eagle2 attains a ≈20x speedup and ≈10% increase in accuracy compared to reference-based phasing using SHAPEIT2. On European-ancestry samples, Eagle2 with the HRC panel achieves >2x the accuracy of 1000 Genomes-based phasing. Eagle2 is open source and freely available for HRC-based phasing via the Sanger Imputation Service and the Michigan Imputation Server.en-USJournal Article2017-05-0110.1038/ng.3679