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Genome Res. 2015 Jun;25(6):792-801. doi: 10.1101/gr.185041.114. Epub 2015 Apr 16.

Characteristics of de novo structural changes in the human genome.

Author information

1
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands;
2
Department of Genome Sciences, University of Washington, Seattle, Washington 98105, USA;
3
Life Sciences Group, Centrum voor Wiskunde en Informatica, Amsterdam 1098XG, The Netherlands;
4
Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands;
5
Department of Biological Psychology, VU University Amsterdam, Amsterdam 1081BT, The Netherlands;
6
Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
7
Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
8
Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
9
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA;
10
Department of Biology, Tufts University, Medford, Massachusetts 02115, USA;
11
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA; Department of Mathematics, Washington University, St. Louis, Missouri 63108, USA;
12
Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000CA, The Netherlands;
13
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;
14
Department of Human Genetics, Leiden University Medical Center, Leiden 2300RC, The Netherlands;
15
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;
16
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA;
17
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713AD, The Netherlands.

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.

PMID:
25883321
PMCID:
PMC4448676
DOI:
10.1101/gr.185041.114
[Indexed for MEDLINE]
Free PMC Article

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