Fig. 1. Mutations in offspring of younger fathers are biased towards later replicating regions.

a. Mean replication timing of de novo mutations in each of the 258 offspring as a function of their father's age. The green line shows the least-square regression line (p = 0.0033) and the grey area the 95% confidence interval. The downward slope of the regression line indicates a shift of mutations towards earlier replicating regions with advancing paternal age.

b. The mean replication timing profile around de novo mutations, stratified by paternal age (orange: under the age of 28, N = 3,697, blue: aged 28 or older, N = 7,323). The grey area shows the null expectation based on simulations (mean ±1 standard deviation). The age of the split between younger and older fathers was chosen to maximize the difference between the groups (p = 5.7 × 10^–4, 23 tests). Mutations in younger fathers tend to be located in large (~2Mb) regions of late-replicating DNA. In contrast, the replication timing distribution of mutations in older fathers is similar to that of simulated mutations. Together, this shows that de novo mutations in offspring of younger fathers are biased towards late-replicating regions, while those in offspring of older fathers are not.