title: A high-quality human reference panel reveals the complexity and distribution of genomic structural variants.
abstract: Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals.
authors.affiliation: Department of Human Genetics, Donders Institute, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Center for Bioinformatics, Saarland University, Saarbrücken 66123, Germany.|Max Plank Institute for Informatics, Saarbrücken 66123, Germany.
authors.forename: Tobias
authors.identifier: 0000-0002-9376-1030
authors.initials: T
authors.lastname: Marschall
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|The Broad Institute, Cambridge, Massachusetts 02142, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Laurent C
authors.initials: LC
authors.lastname: Francioli
authors.affiliation: Life Sciences Group, Centrum Wiskunde &Informatica, Amsterdam 1098XG, The Netherlands.
authors.forename: Jasmijn A
authors.initials: JA
authors.lastname: Baaijens
authors.affiliation: Life Sciences Group, Centrum Wiskunde &Informatica, Amsterdam 1098XG, The Netherlands.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dijkstra
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam 1081BT, The Netherlands.
authors.forename: Abdel
authors.initials: A
authors.lastname: Abdellaoui
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands.
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Koval
authors.affiliation: Department of Human Genetics, Donders Institute, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands.
authors.forename: Djie Tjwan
authors.initials: DT
authors.lastname: Thung
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713AD, The Netherlands.|Groningen Bioinformatics Centre, University of Groningen, Groningen 9747AG, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Wardenaar
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.affiliation: Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle 98105, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen 9700RB, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.
authors.forename: Joep
authors.identifier: 0000-0002-0348-419X
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands.
authors.forename: Eric-Wubbo
authors.initials: EW
authors.lastname: Lameijer
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen 9700RB, The Netherlands.|Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: van Dijk
authors.affiliation: Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle 98105, USA.
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Genome Sciences and Howard Hughes Medical Institute, University of Washington, Seattle 98105, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, The Netherlands.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen 9700RB, The Netherlands.|Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen 9700RB, The Netherlands.
authors.forename: Cisca
authors.identifier: 0000-0002-5635-1614
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands.
authors.forename: Gert-Jan B
authors.initials: GB
authors.lastname: van Ommen
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam 1081BT, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Life Sciences Group, Centrum Wiskunde &Informatica, Amsterdam 1098XG, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schönhuth
authors.affiliation: The Genome Institute, Washington University, St Louis, Missouri 63108, USA.|School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an 710049, China.|The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713AD, The Netherlands.
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
mesh_terms: D000465:Algorithms; D002875:Chromosomes / Q000648:ultrastructure; D019295:Computational Biology; D017353:Gene Deletion; D015894:Genome, Human; D056914:Genomic Structural Variation; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D015810:Linkage Disequilibrium; D009426:Netherlands; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D012984:Software
chemical_list: D012313:RNA