Rate of de novo mutations and the importance of father's age to disease risk

Abstract

Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.

Figure 1. A summary of the family types

a Fifty-seven simple trios. b Six sib pairs accounting for 12 trios. c Five three generation families accounting for 9 trios.

Figure 2. Father‘s age and number of de novo mutations

Number of de novo mutations called is plotted against father's age at conception of child for the 78 trios. The solid black line denotes the linear fit. The broken red curve is based on an exponential model fitted to the combined mutation counts. The broken blue curve corresponds to a model where maternal mutations are assumed to have a constant rate of 14.2 and paternal mutations assumed to increase expoenentially with father‘s age. ♦ proband autistic; proband schizophrenic; proband a parent of an autistic case; □ others.

Figure 3. Effect of father‘s age by chromosome

By chromosome, the estimated increase in the number of de novo mutations per year of father‘s age is plotted against the average number of mutations observed. 95% confidence intervals are given. The solid straight line corresponds to the model where the additive effect of father‘s age on the number of de novo mutations is assumed to be proportional to the mean number of mutations on the chromosome. From left to right, the points correspond to chromsome 21, 22, 19, 20, 15, 17, 18, 14, 16, 13, 12, 9, 10, 11, 8, 7, 6, 3, 5, 4, 2, and 1.

Figure 4. Demographics of Iceland and de novo mutations

The deCODE Genetics genealogy database was used to assess fathers' age at conception for all available 752,343 father-child pairs, where the child's birthyear was ≥1650. The mean age of fathers at conception (left vertical axis) is plotted by birthyear of child, grouped into 10 year intervals. Based on the linear model fitted for the relationship between father's age and the number of de novo mutations, the same plot, using the right vertical axis, shows the mean number of expected mutations for each 10 year interval.