TY - JOUR
T1 - Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing
AU - Ferreira, Pedro G.
AU - Oti, Martin
AU - Barann, Matthias
AU - Wieland, Thomas
AU - Ezquina, Suzana
AU - Friedländer, Marc R.
AU - Rivas, Manuel A.
AU - Esteve-Codina, Anna
AU - Rosenstiel, Philip
AU - Strom, Tim M.
AU - Lappalainen, Tuuli
AU - Guigó, Roderic
AU - Sammeth, Michael
AU - Estivil, Xavier
AU - Dermitzakis, Emmanouil
AU - Antonarakis, Stylianos
AU - Meitinger, Thomas
AU - Palotie, Aarno
AU - Deleuze, Jean Francois
AU - Sudbrak, Ralf
AU - Lerach, Hans
AU - Gut, Ivo
AU - Syvanen, Ann Christine
AU - Gyllensten, Ulf
AU - Schreiber, Stefan
AU - Brunner, Han
AU - Veltman, Joris
AU - Hoen, Peter A.C.T.
AU - Van Ommen, Gert Jan
AU - Carracedo, Angel
AU - Brazma, Alvis
AU - Flicek, Paul
AU - Cambon-Thomsen, Anne
AU - Mangion, Jonathan
AU - Bentley, David
AU - Hamosh, Ada
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/9/12
Y1 - 2016/9/12
N2 - 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.
AB - 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.
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U2 - 10.1038/srep32406
DO - 10.1038/srep32406
M3 - Article
C2 - 27617755
AN - SCOPUS:84987596952
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 32406
ER -