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Reference-based phasing using the Haplotype Reference Consortium panel


Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing in a genotyped cohort, an approach that can yield 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 20× speedup and 10% increase in accuracy compared to reference-based phasing using SHAPEIT2. On European-ancestry samples, Eagle2 with the HRC panel achieves >2× 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.

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Figure 1: Schematic of the Eagle2 core phasing algorithm.
Figure 2: Running time and accuracy of reference-based phasing in UK Biobank benchmarks.
Figure 3: Accuracy of reference-based phasing in GERA benchmarks.
Figure 4: Accuracy of reference-based phasing using the 1000 Genomes and HRC panels.
Figure 5: Running time and accuracy of cohort-based phasing in the UK Biobank cohort.

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We are grateful to S. Linderman, N. Patterson, L. O'Connor, A. Gusev, and B. van de Geijn for helpful discussions. This research was conducted using the UK Biobank Resource. P.L., P.P., and A.L.P. were supported by US National Institutes of Health grants R01 HG006399 and R01 MH101244 and fellowship F32 HG007805. P.D., S.M., R.D., and the Sanger Institute HRC server were supported by Wellcome Trust grant WT098051. C.F., G.R.A., and the Michigan Imputation Server were supported by the Austrian Science Fund (FWF) grant J-3401 and US National Institutes of Health grants HG007022 and HL117626. H.K.F. was supported by the Fannie and John Hertz Foundation. Computational analyses were performed on the Orchestra High Performance Compute Cluster at Harvard Medical School, which is partially supported by grant NCRR 1S10RR028832-01, and on the Lisa Genetic Cluster Computer hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003, principal investigator D. Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam.

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Authors and Affiliations



P.-R.L. and A.L.P. designed the study. P.-R.L., P.F.P., Y.A.R., and H.K.F. developed the algorithm. P.-R.L. wrote the software. P.-R.L. and P.D. performed experiments. P.D. and S.M. incorporated the software into the Sanger Imputation Service. C.F., S.S., and L.F. incorporated the software into the Michigan Imputation Server. All authors analyzed data and wrote the paper.

Corresponding authors

Correspondence to Po-Ru Loh or Alkes L Price.

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The authors declare no competing financial interests.

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Supplementary Figures 1 and 2, Supplementary Tables 1–13 and Supplementary Note. (PDF 1968 kb)

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Loh, PR., Danecek, P., Palamara, P. et al. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet 48, 1443–1448 (2016).

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