Timing, rates and spectra of human germline mutation

Raheleh Rahbari, Arthur Wuster, Sarah J. Lindsay, Robert J. Hardwick, Ludmil B. Alexandrov, Saeed Al Turki, Anna Dominiczak, Andrew Morris, David Porteous, Blair Smith, Michael R. Stratton, Matthew E. Hurles, Scott Wilson

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)126-133
Number of pages8
JournalNature Genetics
Volume48
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

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Germ-Line Mutation
Mutation Rate
Mutation
Paternal Age
Germ Cells
Genome
Inborn Genetic Diseases
Spermatogenesis
Cell Division
Methylation
Embryonic Development
Meta-Analysis
Recurrence

Cite this

Rahbari, R., Wuster, A., Lindsay, S. J., Hardwick, R. J., Alexandrov, L. B., Al Turki, S., ... Wilson, S. (2016). Timing, rates and spectra of human germline mutation. Nature Genetics, 48(2), 126-133. https://doi.org/10.1038/ng.3469
Rahbari, Raheleh ; Wuster, Arthur ; Lindsay, Sarah J. ; Hardwick, Robert J. ; Alexandrov, Ludmil B. ; Al Turki, Saeed ; Dominiczak, Anna ; Morris, Andrew ; Porteous, David ; Smith, Blair ; Stratton, Michael R. ; Hurles, Matthew E. ; Wilson, Scott. / Timing, rates and spectra of human germline mutation. In: Nature Genetics. 2016 ; Vol. 48, No. 2. pp. 126-133.
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Rahbari, R, Wuster, A, Lindsay, SJ, Hardwick, RJ, Alexandrov, LB, Al Turki, S, Dominiczak, A, Morris, A, Porteous, D, Smith, B, Stratton, MR, Hurles, ME & Wilson, S 2016, 'Timing, rates and spectra of human germline mutation' Nature Genetics, vol. 48, no. 2, pp. 126-133. https://doi.org/10.1038/ng.3469

Timing, rates and spectra of human germline mutation. / Rahbari, Raheleh; Wuster, Arthur; Lindsay, Sarah J.; Hardwick, Robert J.; Alexandrov, Ludmil B.; Al Turki, Saeed; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R.; Hurles, Matthew E.; Wilson, Scott.

In: Nature Genetics, Vol. 48, No. 2, 01.02.2016, p. 126-133.

Research output: Contribution to journalArticle

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Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S et al. Timing, rates and spectra of human germline mutation. Nature Genetics. 2016 Feb 1;48(2):126-133. https://doi.org/10.1038/ng.3469