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

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  • David S. M. Lee

    (University of Pennsylvania)

  • Louis R. Ghanem

    (The Children’s Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine)

  • Yoseph Barash

    (University of Pennsylvania
    University of Pennsylvania)

Abstract

G-quadruplex (G4) sequences are abundant in untranslated regions (UTRs) of human messenger RNAs, but their functional importance remains unclear. By integrating multiple sources of genetic and genomic data, we show that putative G-quadruplex forming sequences (pG4) in 5’ and 3’ UTRs are selectively constrained, and enriched for cis-eQTLs and RNA-binding protein (RBP) interactions. Using over 15,000 whole-genome sequences, we find that negative selection acting on central guanines of UTR pG4s is comparable to that of missense variation in protein-coding sequences. At multiple GWAS-implicated SNPs within pG4 UTR sequences, we find robust allelic imbalance in gene expression across diverse tissue contexts in GTEx, suggesting that variants affecting G-quadruplex formation within UTRs may also contribute to phenotypic variation. Our results establish UTR G4s as important cis-regulatory elements and point to a link between disruption of UTR pG4 and disease.

Suggested Citation

  • David S. M. Lee & Louis R. Ghanem & Yoseph Barash, 2020. "Integrative analysis reveals RNA G-quadruplexes in UTRs are selectively constrained and enriched for functional associations," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14404-y
    DOI: 10.1038/s41467-020-14404-y
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    Cited by:

    1. Prakash Kharel & Marta Fay & Ekaterina V. Manasova & Paul J. Anderson & Alexander V. Kurkin & Junjie U. Guo & Pavel Ivanov, 2023. "Stress promotes RNA G-quadruplex folding in human cells," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Ilias Georgakopoulos-Soares & Guillermo E. Parada & Hei Yuen Wong & Ragini Medhi & Giulia Furlan & Roberto Munita & Eric A. Miska & Chun Kit Kwok & Martin Hemberg, 2022. "Alternative splicing modulation by G-quadruplexes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Scott D. Findlay & Lindsay Romo & Christopher B. Burge, 2024. "Quantifying negative selection in human 3ʹ UTRs uncovers constrained targets of RNA-binding proteins," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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