G-quadruplex-forming sequences as potential drivers of genetic diversity in primate protein coding genes

ABSTRACT While non-coding G-quadruplexes (G4s) act as conserved regulatory elements when located in gene promoter and splice sites, the G4 evolutionary conservation in protein coding regions have been low explored. To address the evolutionary dynamics acting on coding G4, we mapped and characterized potential G4-forming sequences across twenty-four primate’s gene orthologous. We found that potentially more stable G4 motifs exist in coding regions following a species-specific trend. Moreover, these motifs depicted the least conserved sites across primates at both the DNA and amino acid levels and are characterized by an indel-rich mutational pattern. This trend was not observed for less stable G4 motifs. A deeper analysis revealed that [G >=3 N 1 ] 4 motifs, depicting potentially most stable G4s, were associated with the lowest conservation and highest indel frequencies. This mutational pattern was more evident when G4-associated amino acid regions were analyzed. We discuss the possibility of an overall conservation of less/moderate stability G4, while more stable G4 may be preserved or arises in a species-specific manner, which may explain their low conservation. Since structure-prone motifs, including G4, have the potential to induce genomic instability, this evolutionary trend may contribute to avoid broad deleterious effects driven by stable G4 on protein function while promoting genetic diversity across close-related species.