Elevated variant density around SV breakpoints in germline lineage lends support to error-prone replication...

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Copy number variants (CNVs) are structural genomic alterations.
• CNVs may involve complex genomic rearrangements (CGRs) and associated mutations.
• Understanding CNV formation is crucial for cell repair, mutation mechanisms, evolution, and disease.

Purpose of the Study:

• To investigate the relationship between copy number variants (CNVs) and flanking genetic variations.
• To test the hypothesis that CNV formation involves error-prone mutational mechanisms.

Main Methods:

• Analysis of heterozygous germline deletions in human genomes (1000 Genomes Project).
• Integration of synthetic long-read and high-coverage short-read data.
• Phasing deletions with flanking single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) by comparing with parental genomes.

Main Results:

• A higher density of in-phase SNPs/indels was observed flanking deletion breakpoints compared to out-of-phase variants.
• This density increase was more pronounced for deletions with replication-based formation signatures.
• Allele frequency spectra indicated an enrichment of rare deletions and a shift in in-phase SNP/indel frequencies, supporting concomitance with deletion events.

Conclusions:

• Findings support the hypothesis that CNV formation mechanisms are error-prone.
• Results may help resolve human mutation-rate discrepancies and explain phenomena like kataegis.