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.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Po-Ru
PR
Loh
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Petr
P
Danecek
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Pier Francesco
PF
Palamara
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated with the University of Lübeck, Bolzano, Italy.|Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Christian
C
Fuchsberger
Department of Computer Science, Harvard University, Cambridge, Massachusetts, USA.
Yakir
Y
A Reshef
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Hilary
H
K Finucane
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Sebastian
S
Schoenherr
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Lukas
L
Forer
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Shane
0000-0002-2715-4187
S
McCarthy
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
Goncalo R
GR
Abecasis
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Richard
0000-0002-9130-1006
R
Durbin
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Alkes
A
L Price
D000465:Algorithms; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D012016:Reference Values
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