Quantification of G-quadruplex Motifs in Human PKD1 Gene as Indicator of Genetic Instability
Dobry, Julia K.
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Polycystic kidney disease (PKD) is a prevalent genetic disorder that leads to the development of fluid-filled cysts on the kidney and other organs, causing enlargement of the kidney and potentially renal failure. The disease can be inherited as the recessive or dominant form. The dominant form, ADPKD, is one the most common genetic diseases, and is linked in mutations in the PKD1 and PKD2 genes in humans. Previous studies have shown that in murine models, none of the genetic forms of murine PKD can be traced back to the murine ortholog Pkd1 gene, suggesting that it is genetically stable. This means that the murine ortholog has a low vulnerability to mutation, unlike the human gene. Other studies have determined that G-quadruplexes, secondary DNA structures characterized by stacked tetrads of coplanar guanine, are able to interrupt DNA replication causing genetic instability and increased vulnerability to mutation. Through in silico analysis of the genes, it was determined that the human PKD1 had a higher frequency of G/C triplets and G4 motifs relative to the mouse or rat Pkd1 gene. It was also observed that the G4 motifs within the human gene were widespread throughout the gene with the exception of two clusters. These observations support the hypothesis that instability of the human PKD1 gene may be related to the presence of G-quadruplex structures. Further investigations must examine the roles of alternative DNA structures in vivo in this pathway. Elucidation of the mechanisms of G-quadruplex structures in PKD1 may offer a potential avenue for drug therapy for ADPKD.