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Association of Z-RNA with QTL variants
Z-DNA and Z-RNA, or Z-flipons, have been shown to play an important role in many cellular processes. Recently the whole-genome map of Z-DNA was generated with Z-DNABERT based on transformer algorithm and trained on the experimental permanganate/S1 nuclease dataset [1]. It was demonstrated how predicted Z-flipons containing single nucleotide variants may affect Z-RNA formation and phenotype. Here we performed analysis of Z-DNABERT predicted Z-flipons that have variants reported in GWAS studies and overlap with expression and splicing QTL in different tissues. We analyzed around 70 DNA variants mapped to the predicted Z-flipons and found that half of them do not affect Z-RNA formation and presumably has an effect at the DNA level. For the remaining the effect was seen at the level of RNA formation. We discovered variants associated with various diseases: pulse pressure, atrial fibrillation and atrial flutter (rs74181299(T>C)), height, thumb osteoarthritis and hip circumference adjusted for BMI (rs11588850(A>G)), sleep duration (short sleep) (rs205024(C>T)), low density lipoprotein cholesterol levels and total cholesterol levels (rs72658867(G>A)), Youthful appearance, schizophrenia (rs138880(A>C)). All the reported variants affect Z-RNA formation by disrupting RNA stems regardless of short or long RNA sequence length is considered. They are often located in the introns and influence expression of other genes in the regions. Some of the reported variants also affect splicing of the same gene they are in or nearby genes. Additionally, we performed haplotype analysis and showed that other variants that are included in the haplotype do not overlap with any known functional genomic elements. Overall, our analysis highlights the potential association of Z-flipons with diseases.