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

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, Xavier Estivil, Emmanouil Dermitzakis, Stylianos Antonarakis, Thomas Meitinger, Aarno Palotie, Jean Francois Deleuze, Ralf Sudbrak & 16 others Hans Lerach, Ivo Gut, Ann Christine Syvanen, Ulf Gyllensten, Stefan Schreiber, Han Brunner, Joris Veltman, Peter A C T Hoen, Gert Jan Van Ommen, Angel Carracedo, Alvis Brazma, Paul Flicek, Anne Cambon-Thomsen, Jonathan Mangion, David Bentley, Ada Hamosh

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number32406
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 12 2016

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RNA
Genome
DNA Sequence Analysis
Cataloging
RNA Editing
RNA Sequence Analysis
RNA Splice Sites
Poly A
Genetic Markers
Computer Simulation
Introns
Alleles
Technology
Phenotype
Gene Expression
Costs and Cost Analysis
Messenger RNA
DNA
Population

ASJC Scopus subject areas

  • General

Cite this

Ferreira, P. G., Oti, M., Barann, M., Wieland, T., Ezquina, S., Friedländer, M. R., ... Hamosh, A. (2016). Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. Scientific Reports, 6, [32406]. https://doi.org/10.1038/srep32406

Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. / Ferreira, Pedro G.; Oti, Martin; Barann, Matthias; Wieland, Thomas; Ezquina, Suzana; Friedländer, Marc R.; Rivas, Manuel A.; Esteve-Codina, Anna; Rosenstiel, Philip; Strom, Tim M.; Lappalainen, Tuuli; Guigó, Roderic; Sammeth, Michael; Estivil, Xavier; Dermitzakis, Emmanouil; Antonarakis, Stylianos; Meitinger, Thomas; Palotie, Aarno; Deleuze, Jean Francois; Sudbrak, Ralf; Lerach, Hans; Gut, Ivo; Syvanen, Ann Christine; Gyllensten, Ulf; Schreiber, Stefan; Brunner, Han; Veltman, Joris; Hoen, Peter A C T; Van Ommen, Gert Jan; Carracedo, Angel; Brazma, Alvis; Flicek, Paul; Cambon-Thomsen, Anne; Mangion, Jonathan; Bentley, David; Hamosh, Ada.

In: Scientific Reports, Vol. 6, 32406, 12.09.2016.

Research output: Contribution to journalArticle

Ferreira, PG, Oti, M, Barann, M, Wieland, T, Ezquina, S, Friedländer, MR, Rivas, MA, Esteve-Codina, A, Rosenstiel, P, Strom, TM, Lappalainen, T, Guigó, R, Sammeth, M, Estivil, X, Dermitzakis, E, Antonarakis, S, Meitinger, T, Palotie, A, Deleuze, JF, Sudbrak, R, Lerach, H, Gut, I, Syvanen, AC, Gyllensten, U, Schreiber, S, Brunner, H, Veltman, J, Hoen, PACT, Van Ommen, GJ, Carracedo, A, Brazma, A, Flicek, P, Cambon-Thomsen, A, Mangion, J, Bentley, D & Hamosh, A 2016, 'Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing', Scientific Reports, vol. 6, 32406. https://doi.org/10.1038/srep32406
Ferreira PG, Oti M, Barann M, Wieland T, Ezquina S, Friedländer MR et al. Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. Scientific Reports. 2016 Sep 12;6. 32406. https://doi.org/10.1038/srep32406
Ferreira, Pedro G. ; Oti, Martin ; Barann, Matthias ; Wieland, Thomas ; Ezquina, Suzana ; Friedländer, Marc R. ; Rivas, Manuel A. ; Esteve-Codina, Anna ; Rosenstiel, Philip ; Strom, Tim M. ; Lappalainen, Tuuli ; Guigó, Roderic ; Sammeth, Michael ; Estivil, Xavier ; Dermitzakis, Emmanouil ; Antonarakis, Stylianos ; Meitinger, Thomas ; Palotie, Aarno ; Deleuze, Jean Francois ; Sudbrak, Ralf ; Lerach, Hans ; Gut, Ivo ; Syvanen, Ann Christine ; Gyllensten, Ulf ; Schreiber, Stefan ; Brunner, Han ; Veltman, Joris ; Hoen, Peter A C T ; Van Ommen, Gert Jan ; Carracedo, Angel ; Brazma, Alvis ; Flicek, Paul ; Cambon-Thomsen, Anne ; Mangion, Jonathan ; Bentley, David ; Hamosh, Ada. / Sequence variation between 462 human individuals fine-tunes functional sites of RNA processing. In: Scientific Reports. 2016 ; Vol. 6.
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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

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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.

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