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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 <jats:italic>in silico<\/jats:italic> 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 <jats:italic>bona fide<\/jats:italic> novel elements of RNA processing\u2014alternative splice sites, introns and cleavage sites\u2014which are often rare and lowly expressed but in other characteristics similar to their annotated counterparts.<\/jats:p>","DOI":"10.1038\/srep32406","type":"journal-article","created":{"date-parts":[[2016,9,12]],"date-time":"2016-09-12T14:06:31Z","timestamp":1473689191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing"],"prefix":"10.1038","volume":"6","author":[{"given":"Pedro G.","family":"Ferreira","sequence":"first","affiliation":[]},{"given":"Martin","family":"Oti","sequence":"additional","affiliation":[]},{"given":"Matthias","family":"Barann","sequence":"additional","affiliation":[]},{"given":"Thomas","family":"Wieland","sequence":"additional","affiliation":[]},{"given":"Suzana","family":"Ezquina","sequence":"additional","affiliation":[]},{"given":"Marc R.","family":"Friedl\u00e4nder","sequence":"additional","affiliation":[]},{"given":"Manuel A.","family":"Rivas","sequence":"additional","affiliation":[]},{"given":"Anna","family":"Esteve-Codina","sequence":"additional","affiliation":[]},{"name":"The GEUVADIS Consortium","sequence":"additional","affiliation":[]},{"given":"Xavier","family":"Estivill","sequence":"additional","affiliation":[]},{"given":"Roderic","family":"Guig\u00f3","sequence":"additional","affiliation":[]},{"given":"Emmanouil","family":"Dermitzakis","sequence":"additional","affiliation":[]},{"given":"Stylianos","family":"Antonarakis","sequence":"additional","affiliation":[]},{"given":"Thomas","family":"Meitinger","sequence":"additional","affiliation":[]},{"given":"Tim M","family":"Strom","sequence":"additional","affiliation":[]},{"given":"Aarno","family":"Palotie","sequence":"additional","affiliation":[]},{"given":"Jean","family":"Fran\u00e7ois Deleuze","sequence":"additional","affiliation":[]},{"given":"Ralf","family":"Sudbrak","sequence":"additional","affiliation":[]},{"given":"Hans","family":"Lerach","sequence":"additional","affiliation":[]},{"given":"Ivo","family":"Gut","sequence":"additional","affiliation":[]},{"given":"Ann-Christine","family":"Syv\u00e4nen","sequence":"additional","affiliation":[]},{"given":"Ulf","family":"Gyllensten","sequence":"additional","affiliation":[]},{"given":"Stefan","family":"Schreiber","sequence":"additional","affiliation":[]},{"given":"Philip","family":"Rosenstiel","sequence":"additional","affiliation":[]},{"given":"Han","family":"Brunner","sequence":"additional","affiliation":[]},{"given":"Joris","family":"Veltman","sequence":"additional","affiliation":[]},{"given":"Peter A.C.T","family":"Hoen","sequence":"additional","affiliation":[]},{"given":"Gert","family":"Jan van Ommen","sequence":"additional","affiliation":[]},{"given":"Angel","family":"Carracedo","sequence":"additional","affiliation":[]},{"given":"Alvis","family":"Brazma","sequence":"additional","affiliation":[]},{"given":"Paul","family":"Flicek","sequence":"additional","affiliation":[]},{"given":"Anne","family":"Cambon-Thomsen","sequence":"additional","affiliation":[]},{"given":"Jonathan","family":"Mangion","sequence":"additional","affiliation":[]},{"given":"David","family":"Bentley","sequence":"additional","affiliation":[]},{"given":"Ada","family":"Hamosh","sequence":"additional","affiliation":[]},{"given":"Philip","family":"Rosenstiel","sequence":"additional","affiliation":[]},{"given":"Tim M","family":"Strom","sequence":"additional","affiliation":[]},{"given":"Tuuli","family":"Lappalainen","sequence":"additional","affiliation":[]},{"given":"Roderic","family":"Guig\u00f3","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Sammeth","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,9,12]]},"reference":[{"key":"BFsrep32406_CR1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev.biochem.72.121801.161720","volume":"72","author":"DL Black","year":"2003","unstructured":"Black, D. 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