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

Pedro G. Ferreira, Martin Oti, Matthias Barann, Thomas Wieland, Suzana Ezquina, Marc R. Friedländer, Manuel A. Rivas, Anna Esteve-Codina, Philip Rosenstiel, Tim M. Strom, Tuuli Lappalainen, Roderic Guigó, Michael Sammeth, Xavier Estivil, Emmanouil Dermitzakis, Stylianos Antonarakis, Thomas Meitinger, Aarno Palotie, Jean Francois Deleuze, Ralf SudbrakHans Lerach, Ivo Gut, Ann Christine Syvanen, Ulf Gyllensten, Stefan Schreiber, Han Brunner, Joris Veltman, Peter A.C.T. Hoen, Gert Jan Van Ommen, Angel Carracedo, Alvis Brazma, Paul Flicek, Anne Cambon-Thomsen, Jonathan Mangion, David Bentley, Ada Hamosh

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Article number32406
JournalScientific Reports
StatePublished - 12 Sep 2016
Externally publishedYes


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