Transcriptome and genome sequencing uncovers functional variation in humans

Tuuli Lappalainen (), Michael Sammeth, Marc R. Friedländer, Peter A. C. ‘t Hoen, Jean Monlong, Manuel A. Rivas, Mar Gonzàlez-Porta, Natalja Kurbatova, Thasso Griebel, Pedro G. Ferreira, Matthias Barann, Thomas Wieland, Liliana Greger, Maarten van Iterson, Jonas Almlöf, Paolo Ribeca, Irina Pulyakhina, Daniela Esser, Thomas Giger, Andrew Tikhonov, Marc Sultan, Gabrielle Bertier, Daniel G. MacArthur, Monkol Lek, Esther Lizano, Henk P. J. Buermans, Ismael Padioleau, Thomas Schwarzmayr, Olof Karlberg, Halit Ongen, Helena Kilpinen, Sergi Beltran, Marta Gut, Katja Kahlem, Vyacheslav Amstislavskiy, Oliver Stegle, Matti Pirinen, Stephen B. Montgomery, Peter Donnelly, Mark I. McCarthy, Paul Flicek, Tim M. Strom, Hans Lehrach, Stefan Schreiber, Ralf Sudbrak, Ángel Carracedo, Stylianos E. Antonarakis, Robert Häsler, Ann-Christine Syvänen, Gert-Jan van Ommen, Alvis Brazma, Thomas Meitinger, Philip Rosenstiel, Roderic Guigó, Ivo G. Gut, Xavier Estivill and Emmanouil T. Dermitzakis ()
Additional contact information
Tuuli Lappalainen: University of Geneva Medical School, 1211 Geneva, Switzerland
Michael Sammeth: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Marc R. Friedländer: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Peter A. C. ‘t Hoen: Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Jean Monlong: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Manuel A. Rivas: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Mar Gonzàlez-Porta: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Natalja Kurbatova: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Thasso Griebel: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Pedro G. Ferreira: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Matthias Barann: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
Thomas Wieland: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Liliana Greger: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Maarten van Iterson: Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Jonas Almlöf: Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Paolo Ribeca: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Irina Pulyakhina: Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Daniela Esser: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
Thomas Giger: University of Geneva Medical School, 1211 Geneva, Switzerland
Andrew Tikhonov: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Marc Sultan: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Gabrielle Bertier: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Daniel G. MacArthur: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Monkol Lek: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Esther Lizano: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Henk P. J. Buermans: Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Ismael Padioleau: University of Geneva Medical School, 1211 Geneva, Switzerland
Thomas Schwarzmayr: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Olof Karlberg: Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Halit Ongen: University of Geneva Medical School, 1211 Geneva, Switzerland
Helena Kilpinen: University of Geneva Medical School, 1211 Geneva, Switzerland
Sergi Beltran: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Marta Gut: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Katja Kahlem: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Vyacheslav Amstislavskiy: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Oliver Stegle: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Matti Pirinen: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Stephen B. Montgomery: University of Geneva Medical School, 1211 Geneva, Switzerland
Peter Donnelly: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Mark I. McCarthy: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Paul Flicek: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Tim M. Strom: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Hans Lehrach: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Stefan Schreiber: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
Ralf Sudbrak: Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
Ángel Carracedo: Fundacion Publica Galega de Medicina Xenomica (SERGAS), Genomic Medicine Group, CIBERER, Universidade de Santiago de Compostela, Santiago de Compostela, Spain
Stylianos E. Antonarakis: University of Geneva Medical School, 1211 Geneva, Switzerland
Robert Häsler: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
Ann-Christine Syvänen: Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
Gert-Jan van Ommen: Leiden University Medical Center, 2300 RC Leiden, the Netherlands
Alvis Brazma: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK
Thomas Meitinger: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Philip Rosenstiel: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany
Roderic Guigó: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Ivo G. Gut: Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
Xavier Estivill: Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
Emmanouil T. Dermitzakis: University of Geneva Medical School, 1211 Geneva, Switzerland

Nature, 2013, vol. 501, issue 7468, 506-511

Abstract: Abstract Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project—the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

Date: 2013
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DOI: 10.1038/nature12531

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