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

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.

Fig 1. Association of parental age with germline DNM.

This figure shows the correlation between different SNV and indel germline DNM (left: germline SNV, right: germline indels) with parental age (Top: paternal age, bottom: maternal age). The X-axis represents the parental age at conception. The Y-axis represents the number of DNM mutations identified through Whole Genome Sequencing.

Fig 2. Association of parental age with CNV called by different algorithms.

We used three different algorithms to detect CNV in our dataset. QuantiSNP was used for genotyping assays while CNVer and BreakDancer were used for WGS. Although the number varies according to which algorithm was used, no difference between young parental age group and old parental group can be detected.