RGD Reference Report - Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. - Rat Genome Database

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

Authors: Ferreira, Pedro G  Oti, Martin  Barann, Matthias  Wieland, Thomas  Ezquina, Suzana  Friedl√§nder, Marc R  Rivas, Manuel A  Esteve-Codina, Anna  GEUVADIS Consortium,   Rosenstiel, Philip  Strom, Tim M  Lappalainen, Tuuli  Guig√≥, Roderic  Sammeth, Michael 
Citation: Ferreira PG, etal., Sci Rep. 2016 Sep 12;6:32406. doi: 10.1038/srep32406.
RGD ID: 18182942
Pubmed: PMID:27617755   (View Abstract at PubMed)
PMCID: PMC5019111   (View Article at PubMed Central)
DOI: DOI:10.1038/srep32406   (Journal Full-text)

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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