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Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence

View ORCID ProfileJakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber
doi: https://doi.org/10.1101/140111
Jakob M. Goldmann
1Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands
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  • ORCID record for Jakob M. Goldmann
Vladimir B. Seplyarskiy
2Division of Genetics, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3Institute for Information Transmission Problems of the Russian Academy of Sciences (Kharkevich Institute), Bolshoi Karetny pereulok 19, Moscow 127994, Russia
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Wendy S.W. Wong
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
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Thierry Vilboux
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
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Dale L. Bodian
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
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Benjamin D. Solomon
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
5Department of Pediatrics, Inova Children’s Hospital, Inova Health System, Falls Church, VA, USA
6Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1201 E Marshall St, Richmond, VA, UAS
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Joris A. Veltman
7Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands
8Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom
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John F. Deeken
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
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Christian Gilissen
7Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands
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John E. Niederhuber
4Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, VA, USA
9Johns Hopkins University School of Medicine, 733 North Broadway Street, Baltimore, MD, USA
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Abstract

Clustering of mutations has been found both in somatic mutations from cancer genomes and in germline de novo mutations (DNMs). We identified 1,755 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios and investigated the underlying mutational mechanisms. We found that the number of clusters on the maternalallele was positively correlated with maternal age and that these consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in regions with an overall increased maternal mutation rate. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G mutations. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions and de novo deletions events. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.

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Posted June 30, 2017.
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Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence
Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber
bioRxiv 140111; doi: https://doi.org/10.1101/140111
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Germline de novo mutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence
Jakob M. Goldmann, Vladimir B. Seplyarskiy, Wendy S.W. Wong, Thierry Vilboux, Dale L. Bodian, Benjamin D. Solomon, Joris A. Veltman, John F. Deeken, Christian Gilissen, John E. Niederhuber
bioRxiv 140111; doi: https://doi.org/10.1101/140111

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