Timing, rates and spectra of human germline mutation

Rahbari, R. et al. (2016) Timing, rates and spectra of human germline mutation. Nature Genetics, 48(2), pp. 126-133. (doi: 10.1038/ng.3469) (PMID:26656846) (PMCID:PMC4731925)

114411.pdf - Accepted Version



Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Morris, Professor Andrew and Dominiczak, Professor Anna
Authors: Rahbari, R., Wuster, A., Lindsay, S. J., Hardwick, R. J., Alexandrov, L. B., Al Turki, S., Dominiczak, A., Morris, A., Porteous, D., Smith, B., Stratton, M. R., and Hurles, M. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Genetics
Publisher:Nature Publishing Group
ISSN (Online):1546-1718
Published Online:14 December 2015
Copyright Holders:Copyright © 2016 Nature Publishing Group
First Published:First published in Nature Genetics 48(2):126-133
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
381721Generation ScotlandAnna DominiczakScottish Executive Health Department (SEHHD-CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES
381724Generation ScotlandAnna DominiczakScottish Executive Health Department (SEHHD-CSO)CZD/16/6RI CARDIOVASCULAR & MEDICAL SCIENCES
407211Genetic healthcare initiativeRichard SinnottScottish Executive Health Department (SEHHD-CSO)CZD/16/6-A MorrIT - E-SCIENCE
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS