Paternal Age Explains a Major Portion of De Novo Germline Mutation Rate Variability in Healthy Individuals

PLoS One. 2016 Oct 10;11(10):e0164212. doi: 10.1371/journal.pone.0164212. eCollection 2016.


De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

MeSH terms

  • Adult
  • DNA / chemistry
  • DNA / isolation & purification
  • DNA / metabolism
  • DNA Copy Number Variations
  • Female
  • Genotype
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Paternal Age*
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA
  • Young Adult


  • DNA

Grant support

Guy A. Rouleau is grateful for the support received through his positions as Canada Research Chair in Genetics of the Nervous System and Jeanne-et-J.-Louis-Levesque Chair for the Genetics of Brain Diseases. Simon L. Girard is grateful for the financial support received from Fonds de Recherche Québec – Santé. This work was also supported by Calcul Québec / Calcul Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.