Thousands of human mutation clusters are explained by short-range template switching

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Human genome variation is unevenly distributed, with variants often spatially clustered.
• DNA replication-associated template switching is an understudied mutational mechanism.
• This mechanism can cause large chromosomal rearrangements and local mutation clusters.

Purpose of the Study:

• To investigate the role of DNA replication-related template switching in human genome variation.
• To develop computational tools for identifying and genotyping template switch events.
• To assess the impact of template switching on mutation detection in genetic studies.

Main Methods:

• Reanalyzed haplotype-resolved genome assemblies from 25 human populations.
• Utilized multinucleotide variants from 140,000 human sequencing experiments.
• Developed novel computational tools for identifying template switch events using short-read and genotype data.

Main Results:

• Local template switching can explain thousands of complex mutation clusters across the human genome.
• These mutation clusters are found at loci segregating within and between human populations.
• Standard analysis pipelines miss template-switch mutations of tens of base pairs, potentially affecting medical genetic studies.

Conclusions:

• Template switching is a significant contributor to human genome mutation patterns.
• Novel computational tools enable cataloging affected loci and studying template switching mechanisms.
• Accurate detection of template-switch mutations is crucial for medical genetic research and understanding disease.