New observations on maternal age effect on germline de novo mutations

Abstract

Germline mutations are the source of evolution and contribute substantially to many health-related processes. Here we use whole-genome deep sequencing data from 693 parents-offspring trios to examine the de novo point mutations (DNMs) in the offspring. Our estimate for the mutation rate per base pair per generation is 1.05 × 10(-8), well within the range of previous studies. We show that maternal age has a small but significant correlation with the total number of DNMs in the offspring after controlling for paternal age (0.51 additional mutations per year, 95% CI: 0.29, 0.73), which was not detectable in the smaller and younger parental cohorts of earlier studies. Furthermore, while the total number of DNMs increases at a constant rate for paternal age, the contribution from the mother increases at an accelerated rate with age.These observations have implications related to the incidence of de novo mutations relating to maternal age.

Figure 1. Parents' age distribution with number of de novo mutations in their offsprings.

(a) The distribution of father's ages at conception (in years). (b) The distribution of mother's ages at conception (in years). (c) The distribution of gestational age for the newborns (in weeks). The colours in each bar in the histograms indicate the proportion of newborns with each number of DNMs in each of the five equally sized bins.

Figure 2. Bar plot of average number of de novo mutations by chromosome.

The average number of DNMs in each autosome are largely correlated with the chromosome sizes. The error bars represent the s.e. of the mean DNMs for each chromosome. Numbers of DNMs in chromosomes 17, 19, 20, 21 and 22 are not significant for either father's or mother's age (P>0.05). Numbers of DNMs in chromosomes 1–4, 6, 8–15 and 18 are significantly correlated with father's age only. Numbers of DNMs in chromosomes 5, 7, 16 are significantly correlated with both parents' ages.

Figure 3. Scatter plots with linear regression line on parental ages and their respective number of de novo mutations in the 61 trios with Illumina sequencing data.

(a) The number of DNMs of paternal origin is plotted against the father's age (in years). The blue line shows the linear fit (estimate of the slope=0.31, P=5.15 × 10⁻⁴) and the grey band represents the 95% confidence interval. (b) The number of DNMs of maternal origin is plotted against the mother's age (in years), the blue line shows the linear fit (estimate of slope=0.12, P=0.02), and the grey band represents the 95% confidence interval.

Figure 4. Partial residual plots on parental ages and number of de novo mutations.

(a) The residuals derived from regressing the number of DNMs on the mother's age are plotted against father's age. The blue line shows the linear fit, the grey band represents the 95% confidence interval. The red line shows the best fit using the Generalized Additive model based on the Generalized Cross Validation (GCV) score. (b) The residuals from regressing the number of DNMs on father's age, plotted against mother's age. The estimated effective degrees of freedom for father's and mother's ages are 1.00 and 1.19, respectively.

Figure 5. Comparison of the three DNM discovery pipelines with Venn diagrams.

(a) The overlap between the list of DNMs called in the 61 trios by CGI custom pipeline (blue circle), Strelka custom pipeline (green circle) and GATK PhaseByTransmission custom pipeline (yellow circle). 1,839 DNMs were called in all 3 custom pipelines and 2,583 DNMs were called in at least 2 custom pipelines. There are 333 (13% of total called by CGI) DNMs uniquely called by the CGI custom pipeline, 103 DNMs (4%) uniquely called by the Strelka custom pipeline and 35 DNMs (1%) uniquely called by the GATK PhaseByTransmission custom pipeline. (b) The overlap between the list of DNMs called in the 61 trios in sites that are considered callable by all 3 custom pipelines, with the same colour scheme as in a. There are 306 (3% of total called by CGI) DNMs uniquely called by the CGI custom pipeline in commonly called bases, 95 DNMs (5%) uniquely called by the Strelka custom pipeline and 29 DNMs (1%) uniquely called by the GATK PhaseByTransmission custom pipeline.