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

Authors:
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
Year of publication:
2016
Volume:
6
Issue:
-
Issn:
2045-2322
Journal title abbreviated:
SCI REP-UK
Journal title long:
Scientific Reports
Impact factor:
4.259
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.