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; Emmanouil T. Dermitzakis

doi:10.1038/nature12531

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 TikhonovMarc 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, Emmanouil T. Dermitzakis

Medicine and Health

Research output: Contribution to journal › Article › peer-review

1396 Scopus citations

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.

Original language	English
Pages (from-to)	506-511
Number of pages	6
Journal	Nature
Volume	501
Issue number	7468
DOIs	https://doi.org/10.1038/nature12531
State	Published - 2013

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/nature12531

Cite this

Lappalainen, T., Sammeth, M., Friedländer, M. R., 'T Hoen, P. A. C., Monlong, J., Rivas, M. A., Gonzàlez-Porta, M., Kurbatova, N., Griebel, T., Ferreira, P. G., Barann, M., Wieland, T., Greger, L., Van Iterson, M., Almlöf, J., Ribeca, P., Pulyakhina, I., Esser, D., Giger, T., ... Dermitzakis, E. T. (2013). Transcriptome and genome sequencing uncovers functional variation in humans. Nature, 501(7468), 506-511. https://doi.org/10.1038/nature12531

@article{1595ec0a9ed74f2aaccea99ae5d661ec,

title = "Transcriptome and genome sequencing uncovers functional variation in humans",

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.",

author = "Tuuli Lappalainen and Michael Sammeth and Friedl{\"a}nder, {Marc R.} and {'T Hoen}, {Peter A.C.} and Jean Monlong and Rivas, {Manuel A.} and Mar Gonz{\`a}lez-Porta and Natalja Kurbatova and Thasso Griebel and Ferreira, {Pedro G.} and Matthias Barann and Thomas Wieland and Liliana Greger and {Van Iterson}, Maarten and Jonas Alml{\"o}f and Paolo Ribeca and Irina Pulyakhina and Daniela Esser and Thomas Giger and Andrew Tikhonov and Marc Sultan and Gabrielle Bertier and Macarthur, {Daniel G.} and Monkol Lek and Esther Lizano and Buermans, {Henk P.J.} and Ismael Padioleau and Thomas Schwarzmayr and Olof Karlberg and Halit Ongen and Helena Kilpinen and Sergi Beltran and Marta Gut and Katja Kahlem and Vyacheslav Amstislavskiy and Oliver Stegle and Matti Pirinen and Montgomery, {Stephen B.} and Peter Donnelly and McCarthy, {Mark I.} and Paul Flicek and Strom, {Tim M.} and Hans Lehrach and Stefan Schreiber and Ralf Sudbrak and {\'A}ngel Carracedo and Antonarakis, {Stylianos E.} and Robert H{\"a}sler and Syv{\"a}nen, {Ann Christine} and {Van Ommen}, {Gert Jan} and Alvis Brazma and Thomas Meitinger and Philip Rosenstiel and Roderic Guig{\'o} and Gut, {Ivo G.} and Xavier Estivill and Dermitzakis, {Emmanouil T.}",

note = "Funding Information: Acknowledgements We would like to thank E. Falconnet, L. Romano, A. Planchon, D. Bielsen, A. Yurovsky, A. Buil, J. Bryois, A. Nica, I. Topolsky, N. Fusi, S. Waszak, C. Bustamante, J. Rung, N. Kolesnikov, A. Roa, E. Bragin, S. Brent, J. Gonzalez, M. Morell, A. Puig, E. Palumbo, M. Ventayol Garcia, J. F. J. Laros, J. Blanc, R. Birkelund, G. Plaja, M. Ingham, J. Camps, M. Bayes, L. Agueda, A. Gouin, M.-L. Yaspo, E. Graf, A. Walther, C. Fischer, S. Loesecke, B. Schmick, D. Balzereit, S. D{\"o}kel, M. Linser, A. Kovacsovics, M. Friskovec, C. von der Lancken, M. Schlapkohl, A. Hellmann, M. Schilhabel, the SNP&SEQ Technology Platform in Uppsala, S. Sauer, the Vital-IT high-performance computing centreofthe SIBSwiss InstituteofBioinformatics,B.Goldstein andothers at the Coriell Institute, and J. Cooper, E. Burnett, K. Ball and others at the European Collection of Cell Cultures (ECACC) and the 1000 Genomes Consortium. This project was funded by the European Commission 7th Framework Program (FP7) (261123; GEUVADIS); the Swiss National Science Foundation (130326, 130342), the Louis Jeantet Foundation, andERC (260927) (E.T.D.); NIH-NIMH (MH090941) (E.T.D., M.I.M., R.G.); Spanish Plan Nacional SAF2008-00357 (NOVADIS), the Generalitat de Catalunya AGAUR 2009 SGR-1502, and the Instituto de Salud Carlos III (FIS/FEDER PI11/00733) (X.E.); Spanish Plan Nacional (BIO2011-26205) and ERC (294653) (R.G.); ESGI, READNA (FP7 Health-F4-2008-201418), Spanish Ministry of Economy and Competitiveness (MINECO) and the Generalitat de Catalunya (I.G.G.); DFG Cluster of Excellence Inflammation at Interfaces, the INTERREG4A project HIT-ID, and the BMBF IHEC project DEEP SP 2.3 (P.Ro.); German Centre for Cardiovascular Research (DZHK) and the German Ministry of Education and Research (01GR0802, 01GM0867, 01GR0804, 16EX1020C) (T.M.); EurocanPlatform (FP7 260791), ENGAGE and CAGEKID (241669) (A.B.); FP7/2007-2013, ENGAGE project, HEALTH-F4-2007-201413, and the Centre for Medical Systems Biology within the framework of The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific and Research (NWO) (P.AC.H and G.-J.v.O.); The Swedish Research Council (C0524801, A028001) and the Knut and Alice Wallenberg Foundation (2011.0073) (A.-C.S.); The Swiss National Science Foundation (127375, 144082) and ERC (249968) (S.E.A.); Instituto de Salud Carlos III (FIS/FEDER PS09/02368) (A.C.); German Federal Ministry of Education and Research (01GS08201) (R.S.); Max Planck Society (H.L.); Wellcome Trust (WT085532) and the European Molecular Biology Laboratory (P.F.); ENGAGE, Wellcome Trust (081917, 090367, 090532, 098381), and Medical Research Council UK (G0601261) (M.I.M.); Wellcome Trust Centre for Human Genetics (090532/Z/09/ Z, 075491/Z/04/B), Wellcome Trust (098381, 090367, 076113, 083270), the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z), Royal Society Wolfson Merit Award, Wellcome Trust Senior Investigator Award (095552/Z/11/Z) (P.D.); EMBO long-term fellowship EMBO-ALTF 2010-337 (H.K.); NIH-NIGMS (R01 GM104371) (D.G.M.); Marie Curie FP7 fellowship (O.S.); Scholarship by the Clarendon Fund of the University of Oxford, and the Nuffield Department of Medicine (M.A.R.); EMBO long-term fellowship ALTF225-2011 (M.R.F.); Emil AaltonenFoundationandAcademy of Finland fellowships (T.L.).",

year = "2013",

doi = "10.1038/nature12531",

language = "English",

volume = "501",

pages = "506--511",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7468",

}

Lappalainen, T, Sammeth, M, Friedländer, MR, 'T Hoen, PAC, Monlong, J, Rivas, MA, Gonzàlez-Porta, M, Kurbatova, N, Griebel, T, Ferreira, PG, Barann, M, Wieland, T, Greger, L, Van Iterson, M, Almlöf, J, Ribeca, P, Pulyakhina, I, Esser, D, Giger, T, Tikhonov, A, Sultan, M, Bertier, G, Macarthur, DG, Lek, M, Lizano, E, Buermans, HPJ, Padioleau, I, Schwarzmayr, T, Karlberg, O, Ongen, H, Kilpinen, H, Beltran, S, Gut, M, Kahlem, K, Amstislavskiy, V, Stegle, O, Pirinen, M, Montgomery, SB, Donnelly, P, McCarthy, MI, Flicek, P, Strom, TM, Lehrach, H, Schreiber, S, Sudbrak, R, Carracedo, Á, Antonarakis, SE, Häsler, R, Syvänen, AC, Van Ommen, GJ, Brazma, A, Meitinger, T, Rosenstiel, P, Guigó, R, Gut, IG, Estivill, X & Dermitzakis, ET 2013, 'Transcriptome and genome sequencing uncovers functional variation in humans', Nature, vol. 501, no. 7468, pp. 506-511. https://doi.org/10.1038/nature12531

TY - JOUR

T1 - Transcriptome and genome sequencing uncovers functional variation in humans

AU - Lappalainen, Tuuli

AU - Sammeth, Michael

AU - Friedländer, Marc R.

AU - 'T Hoen, Peter A.C.

AU - Monlong, Jean

AU - Rivas, Manuel A.

AU - Gonzàlez-Porta, Mar

AU - Kurbatova, Natalja

AU - Griebel, Thasso

AU - Ferreira, Pedro G.

AU - Barann, Matthias

AU - Wieland, Thomas

AU - Greger, Liliana

AU - Van Iterson, Maarten

AU - Almlöf, Jonas

AU - Ribeca, Paolo

AU - Pulyakhina, Irina

AU - Esser, Daniela

AU - Giger, Thomas

AU - Tikhonov, Andrew

AU - Sultan, Marc

AU - Bertier, Gabrielle

AU - Macarthur, Daniel G.

AU - Lek, Monkol

AU - Lizano, Esther

AU - Buermans, Henk P.J.

AU - Padioleau, Ismael

AU - Schwarzmayr, Thomas

AU - Karlberg, Olof

AU - Ongen, Halit

AU - Kilpinen, Helena

AU - Beltran, Sergi

AU - Gut, Marta

AU - Kahlem, Katja

AU - Amstislavskiy, Vyacheslav

AU - Stegle, Oliver

AU - Pirinen, Matti

AU - Montgomery, Stephen B.

AU - Donnelly, Peter

AU - McCarthy, Mark I.

AU - Flicek, Paul

AU - Strom, Tim M.

AU - Lehrach, Hans

AU - Schreiber, Stefan

AU - Sudbrak, Ralf

AU - Carracedo, Ángel

AU - Antonarakis, Stylianos E.

AU - Häsler, Robert

AU - Syvänen, Ann Christine

AU - Van Ommen, Gert Jan

AU - Brazma, Alvis

AU - Meitinger, Thomas

AU - Rosenstiel, Philip

AU - Guigó, Roderic

AU - Gut, Ivo G.

AU - Estivill, Xavier

AU - Dermitzakis, Emmanouil T.

N1 - Funding Information: Acknowledgements We would like to thank E. Falconnet, L. Romano, A. Planchon, D. Bielsen, A. Yurovsky, A. Buil, J. Bryois, A. Nica, I. Topolsky, N. Fusi, S. Waszak, C. Bustamante, J. Rung, N. Kolesnikov, A. Roa, E. Bragin, S. Brent, J. Gonzalez, M. Morell, A. Puig, E. Palumbo, M. Ventayol Garcia, J. F. J. Laros, J. Blanc, R. Birkelund, G. Plaja, M. Ingham, J. Camps, M. Bayes, L. Agueda, A. Gouin, M.-L. Yaspo, E. Graf, A. Walther, C. Fischer, S. Loesecke, B. Schmick, D. Balzereit, S. Dökel, M. Linser, A. Kovacsovics, M. Friskovec, C. von der Lancken, M. Schlapkohl, A. Hellmann, M. Schilhabel, the SNP&SEQ Technology Platform in Uppsala, S. Sauer, the Vital-IT high-performance computing centreofthe SIBSwiss InstituteofBioinformatics,B.Goldstein andothers at the Coriell Institute, and J. Cooper, E. Burnett, K. Ball and others at the European Collection of Cell Cultures (ECACC) and the 1000 Genomes Consortium. This project was funded by the European Commission 7th Framework Program (FP7) (261123; GEUVADIS); the Swiss National Science Foundation (130326, 130342), the Louis Jeantet Foundation, andERC (260927) (E.T.D.); NIH-NIMH (MH090941) (E.T.D., M.I.M., R.G.); Spanish Plan Nacional SAF2008-00357 (NOVADIS), the Generalitat de Catalunya AGAUR 2009 SGR-1502, and the Instituto de Salud Carlos III (FIS/FEDER PI11/00733) (X.E.); Spanish Plan Nacional (BIO2011-26205) and ERC (294653) (R.G.); ESGI, READNA (FP7 Health-F4-2008-201418), Spanish Ministry of Economy and Competitiveness (MINECO) and the Generalitat de Catalunya (I.G.G.); DFG Cluster of Excellence Inflammation at Interfaces, the INTERREG4A project HIT-ID, and the BMBF IHEC project DEEP SP 2.3 (P.Ro.); German Centre for Cardiovascular Research (DZHK) and the German Ministry of Education and Research (01GR0802, 01GM0867, 01GR0804, 16EX1020C) (T.M.); EurocanPlatform (FP7 260791), ENGAGE and CAGEKID (241669) (A.B.); FP7/2007-2013, ENGAGE project, HEALTH-F4-2007-201413, and the Centre for Medical Systems Biology within the framework of The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific and Research (NWO) (P.AC.H and G.-J.v.O.); The Swedish Research Council (C0524801, A028001) and the Knut and Alice Wallenberg Foundation (2011.0073) (A.-C.S.); The Swiss National Science Foundation (127375, 144082) and ERC (249968) (S.E.A.); Instituto de Salud Carlos III (FIS/FEDER PS09/02368) (A.C.); German Federal Ministry of Education and Research (01GS08201) (R.S.); Max Planck Society (H.L.); Wellcome Trust (WT085532) and the European Molecular Biology Laboratory (P.F.); ENGAGE, Wellcome Trust (081917, 090367, 090532, 098381), and Medical Research Council UK (G0601261) (M.I.M.); Wellcome Trust Centre for Human Genetics (090532/Z/09/ Z, 075491/Z/04/B), Wellcome Trust (098381, 090367, 076113, 083270), the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z), Royal Society Wolfson Merit Award, Wellcome Trust Senior Investigator Award (095552/Z/11/Z) (P.D.); EMBO long-term fellowship EMBO-ALTF 2010-337 (H.K.); NIH-NIGMS (R01 GM104371) (D.G.M.); Marie Curie FP7 fellowship (O.S.); Scholarship by the Clarendon Fund of the University of Oxford, and the Nuffield Department of Medicine (M.A.R.); EMBO long-term fellowship ALTF225-2011 (M.R.F.); Emil AaltonenFoundationandAcademy of Finland fellowships (T.L.).

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885645853&partnerID=8YFLogxK

U2 - 10.1038/nature12531

DO - 10.1038/nature12531

M3 - Article

C2 - 24037378

AN - SCOPUS:84885645853

SN - 0028-0836

VL - 501

SP - 506

EP - 511

JO - Nature

JF - Nature

IS - 7468

ER -

Transcriptome and genome sequencing uncovers functional variation in humans

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this