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Nat Genet. 2016 Feb;48(2):126-133. doi: 10.1038/ng.3469. Epub 2015 Dec 14.

Timing, rates and spectra of human germline mutation.

Collaborators (216)

Soranzo N, Timpson N, Spector T, Richards B, Anderson C, Soler Artigas M, Barroso I, Boustred C, Brion MJ, Brown A, Chen L, Clement G, Danecek P, Davey-Smith G, Day I, Day-Williams A, Evans D, Fatemifar G, Flicek P, Franklin C, Gaunt T, Greenwood C, Hart D, He S, Hendricks A, Huang J, Hughes J, Hysi P, Jamshidi Y, Kemp J, Lachance G, Li R, Li Y, Lopes M, Mangino M, Marchini J, McCarthy S, Memari Y, Metrustry S, Min J, Moayyeri A, Northstone K, Panoutsopoulou K, Paternoster L, Perry J, Quaye L, Ring S, Ritchie G, Shin SY, Small K, Southam L, Pourcain BS, Stalker J, Surdulescu G, Tachmazidou I, Tian J, Tobin M, Wain L, Walter K, Wang J, Ward K, Wilson S, Wong K, Zeggini E, Zhang F, Zheng H, Palotie A, Owen M, Barrett J, Rehnström K, Ayub M, Blackwood D, Bolton P, Breen G, Collier D, Craddock N, Crooks L, Curran S, Gallagher L, Geschwind D, Gurling H, Holmans P, Kilpinen H, Kolder I, Lee I, Lönnqvist J, McCarthy S, McGuffin P, McIntosh A, McQuillin A, Muddyman D, O'Donovan M, Parr J, Paunio T, Pietilainen O, Skuse D, Clair DS, Stalker J, Suvisaari J, Walter K, Williams H, Hurles M, Fitzpatrick D, Al-Turki S, Anderson C, Barroso I, Beales P, Bentham J, Bhattacharya S, Carss K, Chatterjee K, Cirak S, Cosgrove C, Daly A, Floyd J, Foley A, Franklin C, Futema M, Humphries S, McCarthy S, Mitchison H, Muntoni F, Onoufriadis A, Parker V, Payne F, Plagnol V, Raymond L, Savage D, Scambler P, Schmidts M, Semple R, Serra E, Stalker J, van Kogelenberg M, Vijayarangakannan P, Walter K, Wood G, Barroso I, Farooqi S, Bochukova E, Hendricks A, McCarthy S, O'Rahilly S, Stalker J, Tachmazidou I, Zeggini E, Zeggini E, Barrett J, Al-Turki S, Anderson C, Asimit J, Barroso I, Crooks L, Day-Williams A, Evans D, Flicek P, Floyd J, Geschwind D, Greenwood C, Hendricks A, Li R, Lopes M, MacArthur D, Memari Y, Metrustry S, Morris J, Palin K, Palotie A, Panoutsopoulou K, Perry J, Rehnström K, Richards B, Ritchie G, Shin SY, Soranzo N, Southam L, Tachmazidou I, Timpson N, Walter K, Wheeler E, Hurles M, Kaye J, Birmingham K, Bobrow M, Bolton P, Durbin R, Fitzpatrick D, Jewell D, Kennedy K, Kent A, Muntoni F, Raymond L, Semple R, Smee C, Spector T, Timpson N, McCarthy S, Stalker J, Langford C, Balasubramaniam S, Burton J, Clapham P, Coates G, Cox T, Danecek P, Edkins S, Ellis P, Jackson D, Jones B, Jorgensen L, Joyce C, Keane T, Maslen J, Quail M, Swerdlow H, Wong K.

Author information

Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Department of Human Genetics and Department of Bioinformatics and Computational Biology, Genentech Inc, 1 DNA Way, CA 94080 South San Francisco, USA.
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Medical Research Institute, University of Dundee, Dundee, United Kingdom.
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Contributed equally


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.

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