Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

Jakob M Goldmann; Juliet E Hampstead; Wendy S W Wong; Amy B Wilfert; Tychele N Turner; Marianne A Jonker; Raphael Bernier; Martijn A Huynen; Evan E Eichler; Joris A Veltman; George L Maxwell; Christian Gilissen

doi:10.1101/gr.271809.120

Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity

Genome Res. 2021 Sep;31(9):1513-1518. doi: 10.1101/gr.271809.120. Epub 2021 Jul 23.

Authors

Jakob M Goldmann^{1

2}, Juliet E Hampstead^{1

2}, Wendy S W Wong³, Amy B Wilfert⁴, Tychele N Turner⁴, Marianne A Jonker⁵, Raphael Bernier⁶, Martijn A Huynen⁷, Evan E Eichler^{4

8}, Joris A Veltman⁹, George L Maxwell¹⁰, Christian Gilissen^{1

2}

Affiliations

¹ Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
² Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
³ Inova Translational Medicine Institute (ITMI), Inova Health Systems, Falls Church, Virginia 22042, USA.
⁴ Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
⁵ Department for Health Evidence, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
⁶ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.
⁷ Centre for Molecular and Biomolecular Informatics, Radboud University Medical Centre, Nijmegen 6525 GA, The Netherlands.
⁸ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
⁹ Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
¹⁰ Department of Obstetrics and Gynecology, Inova Fairfax Department and Inova Schar Cancer Institute, Falls Church, Virginia 22042, USA.

Abstract

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a substantial family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring following correction for parental age. In addition, by modeling DNM data from 1714 multi-offspring families, we estimated that the family-specific contribution explains ∼5.2% of the variation in DNM number. Furthermore, we found no substantial difference between the observed number of DNMs and those predicted by a stochastic Poisson process. We conclude that there is a small family-specific contribution to DNM number and that stochasticity explains a large proportion of variation in DNM counts.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Germ Cells*
Humans
Mutation