Rate of de novo mutations and the importance of father's age to disease risk.
Level 3 - non-randomized controlled study
Non-randomized observational genomic cohort study
PubMed 22914163 · doi:10.1038/nature11396
What was done
The authors sequenced the entire genomes of 78 Icelandic parent-offspring trios at high coverage to measure genome-wide de novo mutation rates and determine the effect of parental age at conception.
What was found
For an average paternal age of 29.7 years, the average de novo mutation rate was 1.20 × 10⁻⁸ per nucleotide per generation. Paternal age at conception dominated the diversity in single nucleotide polymorphism de novo mutation rates, increasing mutation count by approximately two mutations per year of father's age. Paternal mutations were estimated by an exponential model to double every 16.5 years, explaining nearly all variation remaining after accounting for random Poisson variation.
Why it matters
This paper quantitatively establishes paternal age as the primary driver of de novo germline sequence diversity, providing a direct genetic basis for the known association between advancing paternal age and disorders such as autism and schizophrenia.
Limits
The sample is limited to 78 trios from a single homogeneous population (Iceland). The abstract reports on single nucleotide mutations without addressing indels or structural variants, and disease risk is discussed theoretically rather than directly measured against clinical phenotypes in these trios.
Cited by
- supports Advanced paternal age is the most predictive factor for most pathogenic de novo genetic mutations in offspring.
- context De novo mutations in male sperm begin rising at age 18.