Integrative analysis reveals RNA G-quadruplexes in UTRs are selectively constrained and enriched for functional associations

Lee, David S. M.; Ghanem, Louis; Barash, Yoseph

doi:10.1038/s41467-020-14404-y

Cited by 61 publications

(48 citation statements)

References 57 publications

(70 reference statements)

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“…However, the possibility of natural selection acting upon some loci previously considered as neutral is an exciting prospect; the potential functions of such loci should be characterized in future work. In fact, natural selection at some non-B DNA loci has been reported previously ( 24 , 151 )—but the issue remains underexplored to date.…”

Section: Discussionmentioning

confidence: 96%

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Guiblet

Cremona

Harris

et al. 2021

Nucleic Acids Research

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Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B DNA also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation in mutation rates remains unexplored. Here, we conducted a comprehensive analysis of nucleotide substitution frequencies at non-B DNA loci within noncoding, non-repetitive genome regions, their ±2 kb flanking regions, and 1-Megabase windows, using human-orangutan divergence and human single-nucleotide polymorphisms. Functional data analysis at single-base resolution demonstrated that substitution frequencies are usually elevated at non-B DNA, with patterns specific to each non-B DNA type. Mirror, direct and inverted repeats have higher substitution frequencies in spacers than in repeat arms, whereas G-quadruplexes, particularly stable ones, have higher substitution frequencies in loops than in stems. Several non-B DNA types also affect substitution frequencies in their flanking regions. Finally, non-B DNA explains more variation than any other predictor in multiple regression models for diversity or divergence at 1-Megabase scale. Thus, non-B DNA substantially contributes to variation in substitution frequencies at small and large scales. Our results highlight the role of non-B DNA in germline mutagenesis with implications to evolution and genetic diseases.

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Section: Discussionmentioning

confidence: 96%

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Guiblet

Cremona

Harris

et al. 2021

Nucleic Acids Research

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“…Recent research revealed that the G-quadruplexes in human UTRs (untranslated regions) are under selective pressures (Lee et al, 2020), and some coronaviruses on bats and pangolins are closely related to SARS-CoV-2 (Lam et al, 2020;Zhang T. et al, 2020). Consequently, we wondered whether the potential G-quadruplexes in the SARS-CoV-2 genome are under heightened selective constraints.…”

Section: Potential G-quadruplexes Are Under Heightened Selective Consmentioning

confidence: 99%

Whole Genome Identification of Potential G-Quadruplexes and Analysis of the G-Quadruplex Binding Domain for SARS-CoV-2

Zhang

Xiao

et al. 2020

Front. Genet.

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The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has become a global public health emergency. G-quadruplex, one of the non-canonical secondary structures, has shown potential antiviral values. However, little is known about the G-quadruplexes of the emerging SARS-CoV-2. Herein, we characterized the potential G-quadruplexes in both positive and negative-sense viral strands. The identified potential G-quadruplexes exhibited similar features to the G-quadruplexes detected in the human transcriptome. Within some bat- and pangolin-related betacoronaviruses, the G-tracts rather than the loops were under heightened selective constraints. We also found that the amino acid sequence similar to SUD (SARS-unique domain) was retained in SARS-CoV-2 but depleted in some other coronaviruses that can infect humans. Further analysis revealed that the amino acid residues related to the binding affinity of G-quadruplexes were conserved among 16,466 SARS-CoV-2 samples. Moreover, the dimer of the SUD-homology structure in SARS-CoV-2 displayed similar electrostatic potential patterns to the SUD dimer from SARS. Considering the potential value of G-quadruplexes to serve as targets in antiviral strategy, our fundamental research could provide new insights for the SARS-CoV-2 drug discovery.

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“…Lee et al. recently integrated multiple sources of human genomic data and demonstrated that pG4s in 5′ and 3′ mRNA UTRs are selectively constrained, and enriched for cis -expression quantitative trait loci and RBP interactions, implicating rG4s in the mRNA UTRs as important cis-regulatory elements ( 72 ).…”

Section: Evolutionary Distribution Of Rna G-quadruplexesmentioning

confidence: 99%

Properties and biological impact of RNA G-quadruplexes: from order to turmoil and back

Kharel

Becker

Цветков

et al. 2020

Nucleic Acids Research

105

130

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Guanine-quadruplexes (G4s) are non-canonical four-stranded structures that can be formed in guanine (G) rich nucleic acid sequences. A great number of G-rich sequences capable of forming G4 structures have been described based on in vitro analysis, and evidence supporting their formation in live cells continues to accumulate. While formation of DNA G4s (dG4s) within chromatin in vivo has been supported by different chemical, imaging and genomic approaches, formation of RNA G4s (rG4s) in vivo remains a matter of discussion. Recent data support the dynamic nature of G4 formation in the transcriptome. Such dynamic fluctuation of rG4 folding-unfolding underpins the biological significance of these structures in the regulation of RNA metabolism. Moreover, rG4-mediated functions may ultimately be connected to mechanisms underlying disease pathologies and, potentially, provide novel options for therapeutics. In this framework, we will review the landscape of rG4s within the transcriptome, focus on their potential impact on biological processes, and consider an emerging connection of these functions in human health and disease.

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Integrative analysis reveals RNA G-quadruplexes in UTRs are selectively constrained and enriched for functional associations

Cited by 61 publications

References 57 publications

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Whole Genome Identification of Potential G-Quadruplexes and Analysis of the G-Quadruplex Binding Domain for SARS-CoV-2

Properties and biological impact of RNA G-quadruplexes: from order to turmoil and back

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