Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing.
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.
Bioinformatics and Genomics, Center for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.|Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.|Instituto de Investigação e Inovação em Saúde, (i3S) Universidade do Porto, 4200-625 Porto, Portugal.|Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, 4200-625 Porto, Portugal.
Pedro G
PG
Ferreira
Institute of Biophysics Carlos Chagas Filho (IBCCF), Federal University of Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro, Brazil.
Martin
M
Oti
Institute of Clinical Molecular Biology, Christians-Albrechts-Universität zu Kiel, 24105 Kiel, Germany.
Matthias
M
Barann
Institute of Human Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Thomas
T
Wieland
Center for Human Genome and Stem-cell research (HUG-CELL), University of São Paulo (USP), 05508090 São Paulo, Brazil.
Suzana
S
Ezquina
Science for Life Laboratory, Stockholm University, Box 1031, 17121 Solna, Sweden.
Marc R
MR
Friedländer
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
Manuel A
MA
Rivas
Centre Nacional d'Anàlisi Genòmica, 08028 Barcelona, Catalonia, Spain.|Center for Research in Agricultural Genomics (CRAG), Autonome University of Barcelona, 08193 Bellaterra, Catalonia, Spain.
Anna
A
Esteve-Codina
Institute of Clinical Molecular Biology, Christians-Albrechts-Universität zu Kiel, 24105 Kiel, Germany.
Philip
P
Rosenstiel
Institute of Human Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.|Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
Tim M
TM
Strom
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.|Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland.|Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
Tuuli
T
Lappalainen
Bioinformatics and Genomics, Center for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.|Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain.
Roderic
R
Guigó
Bioinformatics and Genomics, Center for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.|Institute of Biophysics Carlos Chagas Filho (IBCCF), Federal University of Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro, Brazil.|National Center of Scientific Computing (LNCC), 2233-6000 Petrópolis, Rio de Janeiro, Brazil.
Michael
M
Sammeth
D000483:Alleles; D017398:Alternative Splicing; D001483:Base Sequence; D005091:Exons; D005787:Gene Frequency; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007438:Introns; D026723:Polyadenylation; D017393:RNA Editing; D022821:RNA Splice Sites; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA
D022821:RNA Splice Sites; D012333:RNA, Messenger