Characteristics of de novo structural changes in the human genome
- Wigard P Kloosterman1,
- Laurent C Francioli1,
- Fereydoun Hormozdiari2,
- Tobias Marschall3,
- Jayne Y Hehir-Kwa4,
- Abdel Abdellaoui5,
- Eric-Wubbo Lameijer6,
- Matthijs H Moed6,
- Vyacheslav Koval7,
- Ivo Renkens1,
- Markus J van Roosmalen1,
- Pascal Arp7,
- Lennart C Karssen7,
- Bradley P Coe2,
- Robert E Handsaker8,
- Eka D Suchiman6,
- Edwin Cuppen1,
- Djie T Thung4,
- Mitch McVey9,
- Michael C Wendl10,
- Andre Uitterlinden7,
- Cornelia M van Duijn7,
- Morris Swertz11,
- Cisca Wijmenga11,
- Gertjan van Ommen6,
- P. Eline Slagboom6,
- Dorret I Boomsma5,
- Alexander Schönhuth12,
- Evan E Eichler2,
- Paul I.W de Bakker1,
- Kai Ye10 and
- Victor Guryev11,13
- 1 UMC Utrecht;
- 2 University of Washington;
- 3 Centrum voor Wiskunde en Informatica;
- 4 Radboud UMC;
- 5 VU University;
- 6 Leiden UMC;
- 7 Erasmus MC;
- 8 Harvard Medical School;
- 9 Tufts University;
- 10 Washington University;
- 11 UMC Groningen;
- 12 Centrum voor Wiskunde er Informatica
- ↵* Corresponding author; email: v.guryev{at}umcg.nl
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 (1-20bp) and 0.16 SVs (>20bp) per generation. De novo structural changes affect on average 4.1kbp 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 non-uniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.
- Received October 1, 2014.
- Accepted April 1, 2015.
- Published by Cold Spring Harbor Laboratory Press
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