Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing

Ferreira, Pedro G.; Oti, Martin; Barann, Matthias; Wieland, Thomas; Ezquina, Suzana; Friedländer, Marc R.; Rivas, Manuel A.; Esteve-Codina, Anna; The GEUVADIS Consortium; Rosenstiel, Philip; Strom, Tim M.; Lappalainen, Tuuli; Guigó Serra, Roderic; Sammeth, Michael

Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing

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dc.contributor.author Ferreira, Pedro G.ca
dc.contributor.author Oti, Martinca
dc.contributor.author Barann, Matthiasca
dc.contributor.author Wieland, Thomasca
dc.contributor.author Ezquina, Suzanaca
dc.contributor.author Friedländer, Marc R.ca
dc.contributor.author Rivas, Manuel A.ca
dc.contributor.author Esteve-Codina, Annaca
dc.contributor.author The GEUVADIS Consortiumca
dc.contributor.author Rosenstiel, Philipca
dc.contributor.author Strom, Tim M.ca
dc.contributor.author Lappalainen, Tuulica
dc.contributor.author Guigó Serra, Rodericca
dc.contributor.author Sammeth, Michaelca
dc.date.accessioned 2017-01-27T08:53:36Z
dc.date.available 2017-01-27T08:53:36Z
dc.date.issued 2016ca
dc.description.abstract Recent advances in the cost-efficiency of sequencing technologies enabled the combined DNA- and RNA-sequencing of human individuals at the population-scale, making genome-wide investigations of the inter-individual genetic impact on gene expression viable. Employing mRNA-sequencing data from the Geuvadis Project and genome sequencing data from the 1000 Genomes Project we show that the computational analysis of DNA sequences around splice sites and poly-A signals is able to explain several observations in the phenotype data. In contrast to widespread assessments of statistically significant associations between DNA polymorphisms and quantitative traits, we developed a computational tool to pinpoint the molecular mechanisms by which genetic markers drive variation in RNA-processing, cataloguing and classifying alleles that change the affinity of core RNA elements to their recognizing factors. The in silico models we employ further suggest RNA editing can moonlight as a splicing-modulator, albeit less frequently than genomic sequence diversity. Beyond existing annotations, we demonstrate that the ultra-high resolution of RNA-Seq combined from 462 individuals also provides evidence for thousands of bona fide novel elements of RNA processing—alternative splice sites, introns, and cleavage sites—which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.
dc.description.sponsorship This research leading to these results has received funding from the European Commission 7th Framework Program, Project N. 261123 (GEUVADIS). PGF received funding by POPH - QREN Type 4.2, European Social Fund and Portuguese Ministry of Science and Technology (MCTES), Contrato Programa no âmbito do Programa Investigador FCT, 2014, IF/01127/2014. MO received funding by the National Counsel of Technological and Scientific Development (CNPq) grant 310132/2015-0, and MS received funding by the Research Support Foundation of the State of Rio de Janeiro (FAPERJ) E_06/2015, and by CNPq grant 401626/2015-6.
dc.format.mimetype application/pdfca
dc.identifier.citation Ferreira PG, Oti M, Barann M, Wieland T, Ezquina S, Friedländer MR et.al. Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. Scientific Reports. 2016;6:32406. DOI: 10.1038/srep32406ca
dc.identifier.doi http://dx.doi.org/10.1038/srep32406
dc.identifier.issn 2045-2322ca
dc.identifier.uri http://hdl.handle.net/10230/28006
dc.language.iso engca
dc.publisher Nature Publishing Groupca
dc.relation.ispartof Scientific Reports. 2016;6:32406
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/261123
dc.rights © Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cell biology
dc.subject.keyword Computational biology and bioinformatics
dc.subject.keyword Molecular biology
dc.title Sequence variation between 462 human individuals fine-tunes functional sites of RNA processingca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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