Characteristics of de novo structural changes in the human genome
- Wigard P. Kloosterman 1 , 18,
- Laurent C. Francioli 1 , 18,
- Fereydoun Hormozdiari 2,
- Tobias Marschall 3,
- Jayne Y. Hehir-Kwa 4,
- Abdel Abdellaoui 5,
- Eric-Wubbo Lameijer 6,
- Matthijs H. Moed 6,
- Vyacheslav Koval 7,
- Ivo Renkens 1,
- Markus J. van Roosmalen 1,
- Pascal Arp 7,
- Lennart C. Karssen 8,
- Bradley P. Coe 2,
- Robert E. Handsaker 9,
- Eka D. Suchiman 6,
- Edwin Cuppen 1,
- Djie Tjwan Thung 4,
- Mitch McVey 10,
- Michael C. Wendl 11 , 12,
- Genome of the Netherlands Consortium 19,
- André Uitterlinden 7 , 8,
- Cornelia M. van Duijn 8,
- Morris A. Swertz 13 , 14,
- Cisca Wijmenga 13 , 14,
- GertJan B. van Ommen 15,
- P. Eline Slagboom 6,
- Dorret I. Boomsma 5,
- Alexander Schönhuth 3,
- Evan E. Eichler 2,
- Paul I.W. de Bakker 1 , 16,
- Kai Ye 11 and
- Victor Guryev 17
- 1Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
- 2Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;
- 3Life Sciences Group, Centrum voor Wiskunde en Informatica, Amsterdam 1098XG, The Netherlands;
- 4Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands;
- 5Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands;
- 6Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
- 7Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
- 8Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
- 9Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 10Department of Biology, Tufts University, Medford, Massachusetts 02115, USA;
- 11The Genome Institute, Washington University, St. Louis, Missouri 63108, USA;
- 12Department of Mathematics, Washington University, St. Louis, Missouri 63108, USA;
- 13Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands;
- 14Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen 9700RB, The Netherlands;
- 15Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
- 16Department of Epidemiology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
- 17European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713AD, The Netherlands
- Corresponding authors: kye{at}genome.wustl.edu, v.guryev{at}umcg.nl
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↵ 18 These authors contributed equally to this work.
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.
Footnotes
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↵ 19 A complete list of consortium authors appears at the end of this article.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.185041.114.
- Received October 1, 2014.
- Accepted April 1, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
