Authors
Arya, A., Datta, B.
Abstract
Symmetry elements in nucleic acids are most strongly correlated with sites of biological function; however, their relevance to non-canonical structures remains underexplored. In this study, we demonstrate the presence and significance of trinucleotide symmetry elements within G-quadruplex (G4) motifs. Our central hypothesis is that the intra-strand mirror symmetry of trinucleotides has been evolutionarily selected to facilitate G4 formation builds on the established sequence-structure association of G-quadruplexes and the natural symmetry law governing nucleotide insertion during genome evolution. Using a conserved G4 motif in the first exon of the MTOR gene as a model, we showed remarkable trinucleotide symmetry preservation across primates and broader mammals, with functional G4 regions displaying locally elevated symmetry relative to the codon-biased exonic background. Analysis of experimentally validated oncogenic G4s, including c-MYC, BCL2, VEGF, and KRAS, revealed that mirror and reverse complement symmetries converge around biologically important G4s. To quantify this feature, we formulated two complementary descriptors: the mirror symmetry index (MSI) and its non-palindromic variant (nMSI). Across 14 oncogene-promoter wild-type G4s, the majority scored MSI [≥] 0.80 (mean 0.884), with only the loop-rich ATG7, BCR, and MDM2 motifs falling below this value, and the KRAS promoter G4 reached individual significance against its mononucleotide-preserving null distribution (p = 0.042). Most decisively, each wild-type G4 scored higher on MSI than its experimentally confirmed G4-abolished mutant in 12 of 14 paired comparisons (sign test, p = 0.0065; mean {Delta}MSI = +0.089, mean {Delta}nMSI = +0.192); the two reversals (BCL2 and HIF-1) are attributable to scrambled mutant controls that introduce more balanced trinucleotide compositions rather than to failure of the index. The directional trend was reproduced across three independently published datasets, with nMSI [≥] 0.50 separating G4-forming from non-G4 sequences at 77.8% sensitivity and 100% specificity, although the collective per-sequence signal from mononucleotide-preserving shuffles remained a non-significant trend (Stouffer combined Z = 1.197, p = 0.116). This first report of trinucleotide symmetry in G4 motifs posits that coordinated nucleotide insertion and quadruplet maintenance act as an evolutionary forcing mechanism that pre-organizes single strands for G4 folding.
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bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Jul 2026.
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