IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v501y2013i7468d10.1038_nature12531.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature12531
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/nature12531?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Guanghao Qi & Benjamin J. Strober & Joshua M. Popp & Rebecca Keener & Hongkai Ji & Alexis Battle, 2023. "Single-cell allele-specific expression analysis reveals dynamic and cell-type-specific regulatory effects," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Katharina T. Schmid & Barbara Höllbacher & Cristiana Cruceanu & Anika Böttcher & Heiko Lickert & Elisabeth B. Binder & Fabian J. Theis & Matthias Heinig, 2021. "scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    3. Chachrit Khunsriraksakul & Daniel McGuire & Renan Sauteraud & Fang Chen & Lina Yang & Lida Wang & Jordan Hughey & Scott Eckert & J. Dylan Weissenkampen & Ganesh Shenoy & Olivia Marx & Laura Carrel & B, 2022. "Integrating 3D genomic and epigenomic data to enhance target gene discovery and drug repurposing in transcriptome-wide association studies," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Chachrit Khunsriraksakul & Qinmengge Li & Havell Markus & Matthew T. Patrick & Renan Sauteraud & Daniel McGuire & Xingyan Wang & Chen Wang & Lida Wang & Siyuan Chen & Ganesh Shenoy & Bingshan Li & Xue, 2023. "Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Anneke Brümmer & Sven Bergmann, 2024. "Disentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Jianping Quan & Ming Yang & Xingwang Wang & Gengyuan Cai & Rongrong Ding & Zhanwei Zhuang & Shenping Zhou & Suxu Tan & Donglin Ruan & Jiajin Wu & Enqin Zheng & Zebin Zhang & Langqing Liu & Fanming Men, 2024. "Multi-omic characterization of allele-specific regulatory variation in hybrid pigs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    7. Chi-Fen Chang & Shu-Pin Huang & Yu-Mei Hsueh & Jiun-Hung Geng & Chao-Yuan Huang & Bo-Ying Bao, 2022. "Genetic Analysis Implicates Dysregulation of SHANK2 in Renal Cell Carcinoma Progression," IJERPH, MDPI, vol. 19(19), pages 1-9, September.
    8. Yuichi Shiraishi & Ai Okada & Kenichi Chiba & Asuka Kawachi & Ikuko Omori & Raúl Nicolás Mateos & Naoko Iida & Hirofumi Yamauchi & Kenjiro Kosaki & Akihide Yoshimi, 2022. "Systematic identification of intron retention associated variants from massive publicly available transcriptome sequencing data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Hanae Sato & Robert H. Singer, 2021. "Cellular variability of nonsense-mediated mRNA decay," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    10. Zhao Wang & Qian Liang & Xinyi Qian & Bolang Hu & Zhanye Zheng & Jianhua Wang & Yuelin Hu & Zhengkai Bao & Ke Zhao & Yao Zhou & Xiangling Feng & Xianfu Yi & Jin Li & Jiandang Shi & Zhe Liu & Jihui Hao, 2023. "An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    11. Hao Wang & Jiaxin Yang & Yu Zhang & Jianliang Qian & Jianrong Wang, 2022. "Reconstruct high-resolution 3D genome structures for diverse cell-types using FLAMINGO," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Ashley Budu-Aggrey & Anna Kilanowski & Maria K. Sobczyk & Suyash S. Shringarpure & Ruth Mitchell & Kadri Reis & Anu Reigo & Reedik Mägi & Mari Nelis & Nao Tanaka & Ben M. Brumpton & Laurent F. Thomas , 2023. "European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Kensuke Yamaguchi & Kazuyoshi Ishigaki & Akari Suzuki & Yumi Tsuchida & Haruka Tsuchiya & Shuji Sumitomo & Yasuo Nagafuchi & Fuyuki Miya & Tatsuhiko Tsunoda & Hirofumi Shoda & Keishi Fujio & Kazuhiko , 2022. "Splicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    14. Nava Ehsan & Bence M. Kotis & Stephane E. Castel & Eric J. Song & Nicholas Mancuso & Pejman Mohammadi, 2024. "Haplotype-aware modeling of cis-regulatory effects highlights the gaps remaining in eQTL data," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    15. Qingbo S. Wang & Ryuya Edahiro & Ho Namkoong & Takanori Hasegawa & Yuya Shirai & Kyuto Sonehara & Hiromu Tanaka & Ho Lee & Ryunosuke Saiki & Takayoshi Hyugaji & Eigo Shimizu & Kotoe Katayama & Masahir, 2022. "The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Jun Inamo & Akari Suzuki & Mahoko Takahashi Ueda & Kensuke Yamaguchi & Hiroshi Nishida & Katsuya Suzuki & Yuko Kaneko & Tsutomu Takeuchi & Hiroaki Hatano & Kazuyoshi Ishigaki & Yasushi Ishihama & Kazu, 2024. "Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    17. Luchang Ming & Debao Fu & Zhaona Wu & Hu Zhao & Xingbing Xu & Tingting Xu & Xiaohu Xiong & Mu Li & Yi Zheng & Ge Li & Ling Yang & Chunjiao Xia & Rongfang Zhou & Keyan Liao & Qian Yu & Wenqi Chai & Sij, 2023. "Transcriptome-wide association analyses reveal the impact of regulatory variants on rice panicle architecture and causal gene regulatory networks," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Yirong Shi & Yiwei Niu & Peng Zhang & Huaxia Luo & Shuai Liu & Sijia Zhang & Jiajia Wang & Yanyan Li & Xinyue Liu & Tingrui Song & Tao Xu & Shunmin He, 2023. "Characterization of genome-wide STR variation in 6487 human genomes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    19. Ke Mao & Christelle Borel & Muhammad Ansar & Angad Jolly & Periklis Makrythanasis & Christine Froehlich & Justyna Iwaszkiewicz & Bingqing Wang & Xiaopeng Xu & Qiang Li & Xavier Blanc & Hao Zhu & Qi Ch, 2023. "FOXI3 pathogenic variants cause one form of craniofacial microsomia," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:501:y:2013:i:7468:d:10.1038_nature12531. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.