G-quadruplex structural variations in human genome associated with single-nucleotide variations and their impact on gene activity

Abstract

G-quadruplexes (G4s) formed by guanine-rich nucleic acids play a role in essential biological processes such as transcription and replication. Besides the >1.5 million putative G-4–forming sequences (PQSs), the human genome features >640 million single-nucleotide variations (SNVs), the most common type of genetic variation among people or populations. An SNV may alter a G4 structure when it falls within a PQS motif. To date, genome-wide PQS–SNV interactions and their impact have not been investigated. Herein, we present a study on the PQS–SNV interactions and the impact they can bring to G4 structures and, subsequently, gene expressions. Based on build 154 of the Single Nucleotide Polymorphism Database (dbSNP), we identified 5 million gains/losses or structural conversions of G4s that can be caused by the SNVs. Of these G4 variations (G4Vs), 3.4 million are within genes, resulting in an average load of >120 G4Vs per gene, preferentially enriched near the transcription start site. Moreover, >80% of the G4Vs overlap with transcription factor–binding sites and >14% with enhancers, giving an average load of 3 and 7.5 for the two regulatory elements, respectively. Our experiments show that such G4Vs can significantly influence the expression of their host genes. These results reveal genome-wide G4Vs and their impact on gene activity, emphasizing an understanding of genetic variation, from a structural perspective, of their physiological function and pathological implications. The G4Vs may also provide a unique category of drug targets for individualized therapeutics, health risk assessment, and drug development.

G-Quadruplex Matters in Tissue-Specific Tumorigenesis by BRCA1 Deficiency

“…The single-molecule visualization of G4s revealed that dynamic G4 formation is associated with transcription, as G4 dynamics are disrupted by the inhibition of transcription [ 40 ]. The same conclusion was derived by a genome-wide interaction study between PQS and single nucleotide variation (SNV) and their impact on transcription [ 92 ]. SNV in PQS can impact the G4 structure, thereby resulting in G4 variation (G4V).…”

“…SNV in PQS can impact the G4 structure, thereby resulting in G4 variation (G4V). The majority of G4Vs overlap with gene regulatory elements, such as transcription factor (TF) binding sites and enhancers, and G4Vs in the regulatory regions have been reported to exhibit a significant influence on gene expression [ 92 ].…”

Genetic variations in G-Quadruplex forming sequences affect the transcription of human disease-related genes

“…Short genetic variants may cause the gain, loss, and/or change in folding propensity of G4s that modulate transcriptional gene expression (25). Therefore, it is a fundamental issue to address the physiological function and pathological implications that such short genetic variations may represent.…”

G-Quadruplexes and the DNA/RNA helicase DHX36 in health, disease, and aging

“…G4 DNA is densely represented in function-specific genomic areas, such as promoters, promoter enhancement regions, oncogenes, and to a high degree, telomeres, all pointing to specific and important functional roles of the G4 structures [ 1 , 2 , 11 ]. Telomeres, G-rich single-stranded 3′ extensions at chromosome ends (TTAGGG) in the form of overhangs, are the most common region in which G4s form.…”