Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
Level 3 - non-randomized controlled study
Observational family-trio genomic sequencing study (by design analogy, not clinical CEBM)
PubMed 28959963 · doi:10.1038/nature24018
What was done
Whole-genome sequencing at 35x coverage was performed on 1,548 Icelanders, their parents, and a subset of 225 individuals with at least one child. Investigators identified single nucleotide polymorphisms and indels, determined parent-of-origin for phased mutations, and evaluated how parental age and sex influenced mutation rates, clustering, mutation types, and genomic distribution.
What was found
A total of 108,778 de novo mutations were identified, with parent of origin assigned for 42,961. Maternal mutations increased by 0.37 per year of age (95% CI 0.32-0.43), compared to 1.51 per year of paternal age (95% CI 1.45-1.57). Maternal mutation clusters accumulated faster with age and covered larger genomic spans than paternal clusters. Maternal mutation composition changed with age, with a 0.26% decrease per year in CpG>TpG mutations (95% CI 0.19-0.33%) and a 0.33% increase per year in C>G mutations (95% CI 0.28-0.38%). A 20-megabase region on chromosome 8p exhibited maternal C>G mutation rates up to 50-fold higher than the genomic baseline, co-localizing with maternal non-crossover gene conversions.
Why it matters
This study shows that maternal age meaningfully shapes the human germline mutation landscape through distinctive mutation types and localized hypermutation regions, expanding the understanding of human sequence diversity beyond paternal replication error models.
Limits
The study is restricted to a single population (Iceland), which may not represent global variation in mutational processes. Parent of origin was determined for only 39.5% (42,961 of 108,778) of detected mutations. The observational sequencing design reports statistical associations between parental age, sex, and mutation characteristics without directly measuring molecular mechanisms.
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.