A sibling study of variation in parental mutation rates

Area of Science:

• Genetics
• Genomic Sequencing
• Human Evolution

Background:

• Individuals inherit variable numbers of de novo germline mutations (DNMs), primarily influenced by parental age.
• Additional factors contributing to DNM variability remain incompletely understood.

Purpose of the Study:

• To develop and apply a novel method for identifying DNMs by comparing sibling genomes in regions inherited identically from both parents.
• To investigate the impact of genetic ancestry, smoking status, and parental DNA repair gene variants on DNM rates and spectra.

Main Methods:

• Whole genome sequencing data from 28,985 sibling pairs and 2,330 trios from UK Biobank and All of Us datasets were analyzed.
• A new approach was used to call DNMs based on nucleotide differences in regions identical by descent between siblings.
• Parental mutation phenotypes were characterized, and associations with variants in 180 DNA repair and maintenance genes were tested.

Main Results:

• Over 800,000 autosomal DNMs were identified across the studied sibling pairs.
• No significant differences in total DNM rates were observed across diverse genetic ancestry groups or between smokers and non-smokers.
• Disruptions in the REV1 and LIG1 genes were significantly associated with increased germline mutation rates in parents.

Conclusions:

• Rare, deleterious variants in DNA repair genes, such as REV1 and LIG1, can act as mutator alleles, increasing germline mutation rates.
• These findings highlight the role of specific gene variants beyond parental age in shaping the germline mutation landscape.
• The study identified specific genetic factors that contribute to the observed variability in de novo germline mutations within human populations.