THE FREQUENCY AND FITNESS OF m6A-ASSOCIATED VARIANTS COULD BE MODULATED BY THE THERMODYNAMIC STABILITY OF AN OVERLAPPING G-QUADRUPLEX

THE FREQUENCY AND FITNESS OF m6A-ASSOCIATED VARIANTS COULD BE MODULATED BY THE THERMODYNAMIC STABILITY OF AN OVERLAPPING G-QUADRUPLEX

Blog Article

Objective: Post-transcriptional modifications like m6A (N6-methyladenosine) and secondary structures like G-quadruplex (G4) are formations that play a vital role in RNA processing.Their synergy also has functional consequences.Since m6A is known to be enzymatically created in the DRACH-motif, and that genetic variants can create a novel DRACH-motif or abolish a pre-existing DRACH-motif, we can hypothesize that variants which affect the gene product level through modulating m6A-G4 colocalization, may also consequently affect fitness and change the allele frequency.To test this hypothesis, the rare and common variants in selected human genes were investigated to determine their effect on DRACH-G4 colocalization.

Material and Methods: Genomic sequences and variant information were retrieved from Ethernet-Over-Power the GRCh37/hg19 and Biomart-Ensembl databases.Experimentally determined G4 sequences were obtained from two different studies.Results: Common variants EMF products leading to the formation of a novel DRACHmotif were found to be significantly higher inside the G4 structure than outside.In contrast, rare variants with the same feature were higher outside the G4-structure and had uneven distribution alongside the premRNA.

The uneven distribution of the DRACH-creating rare variants was observed to correlate with their effect on thermodynamic stability of the overlapping G4.Conclusion: Selective DRACH-G4 colocalization suggests that m6A is evolutionally favorable when overlapping with G4.The thermodynamic stability could lead to uneven distribution of DRACH-G4 colocalization, favorable in 3-prime-side, but not in 5-prime-side.We can conclude that the fitness, and consequently frequency of a DRACH-creating variant is prone to become higher or lower depending in its position and effect on the overlapping-G4 stability.