Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease

Identifying roles for Z-flipons remains challenging given their dynamic nature. Here we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified Z-DNA sequences. We show Z-flipons are enriched in promoters and telomeres and overlap quantitative trait loci for RNA expression, RNA editing, splicing and disease associated variants. Surprisingly, many effects are mediated through Z-RNA formation. We describe Z-RNA motifs present in SCARF2, SMAD1 and CACNA1 transcripts and others in non-coding RNAs. We also provide evidence for another Z-RNA motif that likely enables an adaptive anti-viral intracellular defense through alternative splicing of KRAB domain zinc finger proteins. An analysis of OMIM and gnomAD predicted loss-of-function datasets reveals an overlap of predicted and experimentally validated Z-flipons with disease causing variants in 8.6% and 2.9% of mendelian disease genes respectively, with frameshift variants present in 22% of cases. The work greatly extends the number of phenotypes mapped to Z-flipon variants.