Abstract
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.
Highlights
Untill recently, little was known about the global prevalence of de novo mutations (DNM), and the factors that influence their rate of occurence
We show that rate of germline de novo single nucleotide variants (SNV) and indels but not CNV are associated with parental age
Many groups have shown an association of de novo mutations (DNM) to neurodevelopmental disorders, notably intellectual disability (ID)[14], autism spectrum disorder (ASD)[15,16,17] and schizophrenia[18,19,20]
Summary
Little was known about the global prevalence of de novo mutations (DNM), and the factors that influence their rate of occurence. Some studies suggested that different factors such as pollution, tobacco smoke or magnetic field could impact the global mutation rate [1,2,3], but it was not possible to assess these on a genome-wide scale, or to look at different classes of DNM. New sequencing technologies allow the interrogation of the full genome by sequencing Using these technologies, it was recently demonstrated that paternal age effect (PAE) modulates the DNM rate in patients with psychiatric disorders[4, 5]. It was recently demonstrated that paternal age effect (PAE) modulates the DNM rate in patients with psychiatric disorders[4, 5] We replicate these finding in ten disease free twin quartets. We confirm the existence of DNM hotspots, suggesting new mechanisms for the occurrence of new mutations
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