title: Characteristics of de novo structural changes in the human genome.
abstract: Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Laurent C
authors.initials: LC
authors.lastname: Francioli
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;
authors.forename: Fereydoun
authors.initials: F
authors.lastname: Hormozdiari
authors.affiliation: Life Sciences Group, Centrum voor Wiskunde en Informatica, Amsterdam 1098XG, The Netherlands;
authors.forename: Tobias
authors.initials: T
authors.lastname: Marschall
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands;
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands;
authors.forename: Abdel
authors.initials: A
authors.lastname: Abdellaoui
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
authors.forename: Eric-Wubbo
authors.initials: EW
authors.lastname: Lameijer
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
authors.forename: Matthijs H
authors.initials: MH
authors.lastname: Moed
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 Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Markus J
authors.initials: MJ
authors.lastname: van Roosmalen
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
authors.forename: Pascal
authors.initials: P
authors.lastname: Arp
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
authors.forename: Lennart C
authors.initials: LC
authors.lastname: Karssen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
authors.forename: Eka D
authors.initials: ED
authors.lastname: Suchiman
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands;
authors.forename: Djie Tjwan
authors.initials: DT
authors.lastname: Thung
authors.affiliation: Department of Biology, Tufts University, Medford, Massachusetts 02115, USA;
authors.forename: Mitch
authors.initials: M
authors.lastname: McVey
authors.affiliation: The Genome Institute, Washington University, St. Louis, Missouri 63108, USA; Department of Mathematics, Washington University, St. Louis, Missouri 63108, USA;
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
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
authors.initials: A
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 Genetics, University of Groningen, University Medical Center Groningen, 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: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands; Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands;
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
authors.forename: GertJan 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, VU University Amsterdam, Amsterdam 1081BT, The Netherlands;
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Life Sciences Group, Centrum voor Wiskunde en Informatica, Amsterdam 1098XG, The Netherlands;
authors.forename: Alexander
authors.initials: A
authors.lastname: Schönhuth
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands; Department of Epidemiology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: The Genome Institute, Washington University, St. Louis, Missouri 63108, USA;
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: D000483:Alleles; D000595:Amino Acid Sequence; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D008969:Molecular Sequence Data; D059645:Mutation Rate; D020641:Polymorphism, Single Nucleotide; D018626:Retroelements / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
chemical_list: D018626:Retroelements