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

View ORCID ProfileDavid S.M. Lee, View ORCID ProfileLouis R. Ghanem, View ORCID ProfileYoseph Barash
doi: https://doi.org/10.1101/666842
David S.M. Lee
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Louis R. Ghanem
2Department of Pediatrics, Division of Gastroenterology, Children’s Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104
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  • For correspondence: yosephb@upenn.edu GHANEML@email.chop.edu
Yoseph Barash
1Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
3Department of Computer and Information Science, School of Engineering, University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: yosephb@upenn.edu GHANEML@email.chop.edu
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ABSTRACT

Identifying regulatory elements in the noncoding genome is a fundamental challenge in biology. 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 uncover a degree of negative (purifying) selection in UTR pG4s comparable to that of missense variation in protein-coding sequences. In parallel, we identify new proteins with evidence for preferential binding at pG4s from ENCODE annotations, and delineate putative regulatory networks composed of shared binding targets. Finally, by mapping variants in the NIH GWAS Catalogue and ClinVar, we find enrichment for disease-associated variation in 3’UTR pG4s. At a GWAS pG4-variant associated with hypertension in HSPB7, we uncover robust allelic imbalance in GTEx RNA-seq across multiple tissues, suggesting that changes in gene expression associated with pG4 disruption underlie the observed phenotypic association. Taken together, our results establish UTR G-quadruplexes as important cis-regulatory features, and point to a putative link between disruption within UTR pG4 and susceptibility to human disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 11, 2019.
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Integrative analysis reveals RNA G-Quadruplexes in UTRs are selectively constrained and enriched for functional associations
David S.M. Lee, Louis R. Ghanem, Yoseph Barash
bioRxiv 666842; doi: https://doi.org/10.1101/666842
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Integrative analysis reveals RNA G-Quadruplexes in UTRs are selectively constrained and enriched for functional associations
David S.M. Lee, Louis R. Ghanem, Yoseph Barash
bioRxiv 666842; doi: https://doi.org/10.1101/666842

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