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

Umerenkov, D.; Herbert, A.; Konovalov, D.; Danilova, A.; Beknazarov, N.; Kokh, V.; Fedorov, A.; Poptsova, M.

doi:10.1101/2023.01.12.523822

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bioRxiv · 10.1101/2023.01.12.523822

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

Umerenkov, D.·Herbert, A.·Konovalov, D.·Danilova, A.·Beknazarov, N.·Kokh, V.·Fedorov, A.·Poptsova, M.

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Abstract

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.

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Umerenkov, D., Herbert, A., Konovalov, D., Danilova, A., Beknazarov, N., Kokh, V., Fedorov, A., Poptsova, M.. 2023-01-13. Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease. https://doi.org/10.1101/2023.01.12.523822

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