Characterization of Z-DNA dynamics across the tree of life.

Z-DNA/Z-RNA is an alternative left-handed nucleic acid conformation with established and emerging roles in gene regulation, immunity, and genome instability. However, its occurrence dynamics and lineage specificity across the tree of life have not yet been fully characterized. Utilizing the recently developed and improved Z-DNA searching tool, ZSeeker, we analyzed 281,139 complete organismal genomes, including multiple Telomere-to-Telomere genome assemblies, and generated genome-wide Z-nucleic acid maps, examined their topography, and compared them to dinucleotide-preserving controls. Cellular genomes featured pervasive Z-DNA enrichment relative to expectation, with enrichments of ~1.5 and ~1.7-fold in Bacteria and Archaea and ~3-fold in Eukaryota. In contrast, Viruses exhibited large differences between lineages, with modest enrichment in several DNA viral groups and pronounced depletion across RNA clades, most notably Influenza A/B strains. We built a LASSO regression model trained on non-Influenza viruses (cross-validated R