Multi-nucleotide de novo Mutations in Humans

Area of Science:

• Genetics
• Molecular Biology
• Human Evolution

Background:

• DNA mutation is a fundamental biological process influencing evolution and disease.
• Understanding human mutation rates is crucial for genetic studies and personalized medicine.

Purpose of the Study:

• To estimate the mutation rate of single nucleotide variants (SNVs) and short length variants (indels) in humans.
• To investigate the human mutation process and identify factors influencing mutation occurrence.

Main Methods:

• Analysis of 283 parent-offspring trios to identify de novo mutations.
• Distinguishing between SNVs and indels and quantifying their respective mutation rates.
• Examining mutation patterns, including multi-nucleotide mutations (MNMs) and mutation clustering.

Main Results:

• Estimated SNV mutation rate at 1.29 × 10-8 per position per generation (PPPG).
• Estimated indel mutation rate at 9.29 × 10-10 PPPG.
• Approximately 3% of de novo SNVs are part of MNMs, with mutations often occurring in proximity (median 525bp).
• Higher mutation rates observed in late-replicating genomic regions and near recombination hotspots.

Conclusions:

• Provides precise estimates for human SNV and indel mutation rates.
• Highlights the influence of replication timing and recombination on mutation occurrence.
• Suggests that a significant proportion of mutations occur in clusters or as multi-nucleotide events.