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Transcriptome and genome sequencing uncovers functional variation in humans

Author

Listed:
  • Tuuli Lappalainen

    (University of Geneva Medical School, 1211 Geneva, Switzerland
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland)

  • Michael Sammeth

    (Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain
    Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 08003 Barcelona, Catalonia, Spain)

  • Marc R. Friedländer

    (Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 08003 Barcelona, Catalonia, Spain
    CRG CIBERESP, 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
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 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
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 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
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain)

  • Daniel G. MacArthur

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of Harvard and MIT)

  • Monkol Lek

    (Analytic and Translational Genetics Unit, Massachusetts General Hospital
    Program in Medical and Population Genetics, Broad Institute of Harvard and MIT)

  • Esther Lizano

    (Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 08003 Barcelona, Catalonia, Spain
    CRG CIBERESP, 08003 Barcelona, Catalonia, Spain)

  • Henk P. J. Buermans

    (Leiden University Medical Center, 2300 RC Leiden, the Netherlands
    Leiden Genome Technology Center, 2300 RC Leiden, the Netherlands)

  • Ismael Padioleau

    (University of Geneva Medical School, 1211 Geneva, Switzerland
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinformatics, 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
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland)

  • Helena Kilpinen

    (University of Geneva Medical School, 1211 Geneva, Switzerland
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinformatics, 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
    Present addresses: Bioinformatics Laboratory, National Laboratory of Scientific Computing (LNCC), Petropolis 25651-075, Rio de Janeiro, Brazil (M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, California 94305-5324, USA (S.B.M.); Alacris Theranostics GmbH, 14195 Berlin, Germany (R.S.).)

  • 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
    Oxford Centre for Diabetes Endocrinology and Metabolism, 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
    Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany)

  • Hans Lehrach

    (Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
    Dahlem Centre for Genome Research and Medical Systems Biology, 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
    Dahlem Centre for Genome Research and Medical Systems Biology, 14195 Berlin, Germany
    Present addresses: Bioinformatics Laboratory, National Laboratory of Scientific Computing (LNCC), Petropolis 25651-075, Rio de Janeiro, Brazil (M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, California 94305-5324, USA (S.B.M.); Alacris Theranostics GmbH, 14195 Berlin, Germany (R.S.).)

  • 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
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 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
    Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany
    Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, 81675 Munich, 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
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 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
    Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain
    CRG Hospital del Mar Research Institute, 08003 Barcelona, Catalonia, Spain
    CRG CIBERESP, 08003 Barcelona, Catalonia, Spain)

  • Emmanouil T. Dermitzakis

    (University of Geneva Medical School, 1211 Geneva, Switzerland
    Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland
    Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland)

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.

Suggested Citation

  • 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 & Matthia, 2013. "Transcriptome and genome sequencing uncovers functional variation in humans," Nature, Nature, vol. 501(7468), pages 506-511, September.
    • Handle: RePEc:nat:nature:v:501:y:2013:i:7468:d:10.1038_nature12531
    DOI: 10.1038/nature12531
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