Conserved G-Quadruplex-Forming Sequences in Mammalian TERT Promoters and Their Effect on Mutation Frequency

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Somatic mutations in the human telomerase reverse transcriptase (hTERT) promoter are common in cancers.
• The hTERT promoter contains G-quadruplex (G4) forming sequences, linked to mutagenicity and genome instability.

Purpose of the Study:

• To investigate the presence, conservation, and evolutionary significance of G4 motifs in mammalian TERT promoter regions.
• To determine if G4 motifs contribute to genomic instability and evolutionary adaptation across species.

Main Methods:

• Bioinformatic analysis using QGRS mapper to identify G4 motifs in 1000 bp TERT promoter regions of 141 mammalian species.
• Block alignment approach (Nucleotide PanGenome explorer) to identify conserved G4 motifs and single-nucleotide variants.
• Statistical analysis to compare nucleotide substitution frequencies in conserved G4 motifs versus surrounding regions.

Main Results:

• G4 motifs are primarily located near the transcription start site (up to 400 bp) and are enriched on the non-coding strand of TERT promoters.
• 11-22% of identified G4 motifs are evolutionarily conserved across related mammalian species.
• A statistically significant higher frequency of nucleotide substitutions was observed in conserved G4 motifs compared to flanking regions, specifically in the order Primates.

Conclusions:

• Conserved G4 motifs in mammalian TERT promoters suggest a functional role in genome regulation.
• G4 structures may play a role in DNA repair processes and influence evolutionary adaptation, particularly in primates.
• The findings support the hypothesis that G4s impact genome stability and species evolution.