Origin, frequency and functional impact of de novo structural changes in the human genome. K. Ye1, W. Kloosterman2, L. C. Francioli2, F. Hormozdiari3, T. Marschall4, J. Y. Hehir-Kwa5, A. Abdellaoui6, E. W. Lameijer7, M. H. Moed7, V. Koval8, I. Renkens2, M. J. van Roosmalen2, P. Arp8, L. Karssen9, B. P. Coe3, R. E. Handsaker10, E. Cuppen2, D. T. Thung5, M. C. Wendl1,11, A. Uitterlinden8, C. M. van Duijn9, M. Swertz12,13, C. Wijmenga12,13, G. van Ommen14, P. E. Slagboom7, D. I. Boomsma6, A. Schonhuth5, E. E. Eichler3, P. I. W. de Bakker2,15, V. Guryev16 1) Washington University in St Louis, St Louis, MO; 2) Center for Molecular Medicine, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 3) Department of Genome Sciences, University of Washington, Seattle, USA; 4) Centrum voor Wiskunde en Informatica, Life Sciences Group, Amsterdam, The Netherlands; 5) Department of Human Genetics, Radboud University Medical Center, Nijmegen, Nijmegen, The Netherlands; 6) Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; 7) Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands; 8) Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 9) Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; 10) Department of Genetics, Harvard Medical School, Boston, MA, USA; 11) Department of Mathematics, Washington University, St. Louis, MO, USA; 12) Center Groningen, Department of Genetics, Groningen, The Netherlands; 13) University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands; 14) Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 15) Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands; 16) European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

   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 325 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 2.87 indels (1-20bp) and 0.16 SVs (>20bp) per genome per generation. Structural changes affect 4.1kbp of genomic sequence and 43 coding bases per generation - 65-90 times more nucleotides than de novo substitutions. A significantly larger proportion (66%) of structural changes originated from fathers. Additionally, we observed a non-uniform distribution of de novo SVs across offspring, suggesting unequal familial susceptibility to genomic rearrangements. These results reveal the mechanisms that govern changes in genome structure across generations.

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