Thermodynamically stable and genetically unstable G-quadruplexes are depleted in genomes across species

Abstract G-quadruplexes play various roles in multiple biological processes, which can be positive when a G4 is involved in the regulation of gene expression or detrimental when the folding of a stable G4 impairs DNA replication promoting genome instability. This duality interrogates the significanc...

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Bibliographic Details
Published in:Nucleic acids research 2019-07, Vol.47 (12), p.6098-6113
Main Authors: Puig Lombardi, Emilia, Holmes, Allyson, Verga, Daniela, Teulade-Fichou, Marie-Paule, Nicolas, Alain, Londoño-Vallejo, Arturo
Format: Article
Language:English
Subjects:
Animals
Biochemistry, Molecular Biology
Biodiversity
Bioinformatics
Computational Biology
Computer Science
Eukaryota - genetics
G-Quadruplexes
Genome
Genome, Human
Genomics
Humans
Life Sciences
Mice
Nucleotide Motifs
Polymorphism, Genetic
Populations and Evolution
Quantitative Methods
Thermodynamics
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Summary:Abstract G-quadruplexes play various roles in multiple biological processes, which can be positive when a G4 is involved in the regulation of gene expression or detrimental when the folding of a stable G4 impairs DNA replication promoting genome instability. This duality interrogates the significance of their presence within genomes. To address the potential biased evolution of G4 motifs, we analyzed their occurrence, features and polymorphisms in a large spectrum of species. We found extreme bias of the short-looped G4 motifs, which are the most thermodynamically stable in vitro and thus carry the highest folding potential in vivo. In the human genome, there is an over-representation of single-nucleotide-loop G4 motifs (G4-L1), which are highly conserved among humans and show a striking excess of the thermodynamically least stable G4-L1A (G3AG3AG3AG3) sequences. Functional assays in yeast showed that G4-L1A caused the lowest levels of both spontaneous and G4-ligand-induced instability. Analyses across 600 species revealed the depletion of the most stable G4-L1C/T quadruplexes in most genomes in favor of G4-L1A in vertebrates or G4-L1G in other eukaryotes. We discuss how these trends might be the result of species-specific mutagenic processes associated to a negative selection against the most stable motifs, thus neutralizing their detrimental effects on genome stability while preserving positive G4-associated biological roles.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkz463