Z-DNA-induced genomic instability in the human pangenome

Area of Science:

• Genomics
• Molecular Biology
• Human Genetics

Background:

• Z-DNA is a non-canonical left-handed DNA conformation.
• It plays roles in gene regulation, genomic variation, and genome instability.
• Long-read sequencing advances allow for systematic Z-DNA analysis in complex genomes.

Purpose of the Study:

• To systematically map Z-DNA forming sequences in the human genome.
• To investigate the genomic and mutational landscape of Z-DNA.
• To understand Z-DNA's contribution to genome instability and disease.

Main Methods:

• Leveraged the complete telomere-to-telomere human genome and 464 haplotype-resolved assemblies.
• Systematically mapped Z-DNA forming sequences.
• Analyzed over 52 million variants and 250,000 de novo mutations.

Main Results:

• Z-DNA density is conserved across human haplotypes and superpopulations.
• Z-DNA is enriched in repetitive regions, including centromeric and pericentromeric loci, often unresolved in GRCh38.
• Z-DNA loci show significant enrichment for mutations (insertions, deletions, structural variants) not explained by sequence composition alone.

Conclusions:

• Z-DNA is a functional element within the human genome.
• Z-DNA contributes to genome instability.
• Z-DNA has implications for human disease.