Transcriptome and genome sequencing uncovers functional variation in humans

被引：1355

作者：

Lappalainen, Tuuli ^{[1
,2
,3
]}

Sammeth, Michael ^{[4
,5
,6
,7
]}

Friedlaender, Marc R. ^{[5
,6
,7
,8
]}

't Hoen, Peter A. C. ^{[9
]}

Monlong, Jean ^{[5
,6
,7
]}

Rivas, Manuel A. ^{[10
]}

Gonzalez-Porta, Mar ^{[11
]}

Kurbatova, Natalja ^{[11
]}

Griebel, Thasso ^{[4
]}

Ferreira, Pedro G. ^{[5
,6
,7
]}

Barann, Matthias ^{[12
]}

Wieland, Thomas ^{[13
]}

Greger, Liliana ^{[11
]}

van Iterson, Maarten ^{[9
]}

Almloef, Jonas ^{[14
]}

Ribeca, Paolo ^{[4
]}

Pulyakhina, Irina ^{[9
]}

Esser, Daniela ^{[12
]}

Giger, Thomas ^{[1
]}

Tikhonov, Andrew ^{[11
]}

Sultan, Marc ^{[15
]}

Bertier, Gabrielle ^{[5
,6
]}

MacArthur, Daniel G. ^{[16
,17
]}

Lek, Monkol ^{[16
,17
]}

Lizano, Esther ^{[5
,6
,7
,8
]}

Buermans, Henk P. J. ^{[9
,18
]}

Padioleau, Ismael ^{[1
,2
,3
]}

Schwarzmayr, Thomas ^{[13
]}

Karlberg, Olof ^{[14
]}

Ongen, Halit ^{[1
,2
,3
]}

Kilpinen, Helena ^{[1
,2
,3
]}

Beltran, Sergi ^{[4
]}

Gut, Marta ^{[4
]}

Kahlem, Katja ^{[4
]}

Amstislavskiy, Vyacheslav ^{[15
]}

Stegle, Oliver ^{[11
]}

Pirinen, Matti ^{[10
]}

Montgomery, Stephen B. ^{[1
]}

Donnelly, Peter ^{[10
]}

McCarthy, Mark I. ^{[10
,19
]}

Flicek, Paul ^{[11
]}

Strom, Tim M. ^{[13
,20
]}

Lehrach, Hans ^{[15
,21
]}

Schreiber, Stefan ^{[12
]}

Sudbrak, Ralf ^{[15
,21
]}

Carracedo, Angel ^{[22
]}

Antonarakis, Stylianos E. ^{[1
,2
]}

Haesler, Robert ^{[12
]}

Syvaenen, Ann-Christine ^{[14
]}

Van Ommen, Gert-Jan ^{[9
]}

机构：

[1] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[2] Univ Geneva, iG3, CH-1211 Geneva, Switzerland

[3] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland

[4] Ctr Nacl Anal Genom, Barcelona 08028, Catalonia, Spain

[5] CRG, Barcelona 08003, Catalonia, Spain

[6] UPF, Barcelona 08003, Catalonia, Spain

[7] CRG Hosp del Mar Res Inst, Barcelona 08003, Catalonia, Spain

[8] CRG CIBERESP, Barcelona 08003, Catalonia, Spain

[9] Leiden Univ, Med Ctr, Dept Human Genet, NL-2300 RC Leiden, Netherlands

[10] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[11] EBI, EMBL, Hinxton CB10 1SD, England

[12] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[13] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[14] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, S-75185 Uppsala, Sweden

[15] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[16] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[17] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[18] Leiden Genome Technol Ctr, NL-2300 RC Leiden, Netherlands

[19] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7BN, England

[20] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany

[21] Dahlem Ctr Genome Res & Med Syst Biol, D-14195 Berlin, Germany

[22] Univ Santiago de Compostela, CIBERER, Genom Med Grp, Fdn Publ Galega Med Xen SERGAS, Santiago De Compostela, Spain

[23] Deutsch Forschungszentrum Herz Kreislauferkrankun, Partner Site Munich Heart Alliance, D-81675 Munich, Germany

来源：

NATURE | 2013年 / 501卷 / 7468期

基金：

英国惠康基金; 瑞士国家科学基金会; 欧洲研究理事会; 瑞典研究理事会; 芬兰科学院; 英国医学研究理事会;

关键词：

GENE-EXPRESSION; LANDSCAPE; VARIANTS;

D O I：

10.1038/nature12531

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：506 / 511

页数：6

共 35 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] The Evolutionary Landscape of Alternative Splicing in Vertebrate Species [J].

Barbosa-Morais, Nuno L. ;

Irimia, Manuel ;

Pan, Qun ;

Xiong, Hui Y. ;

Gueroussov, Serge ;

Lee, Leo J. ;

Slobodeniuc, Valentina ;

Kutter, Claudia ;

Watt, Stephen ;

Colak, Recep ;

Kim, TaeHyung ;

Misquitta-Ali, Christine M. ;

Wilson, Michael D. ;

Kim, Philip M. ;

Odom, Duncan T. ;

Frey, Brendan J. ;

Blencowe, Benjamin J. .

SCIENCE, 2012, 338 (6114) :1587-1593

[3] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[4] The impact of retrotransposons on human genome evolution [J].

Cordaux, Richard ;

Batzer, Mark A. .

NATURE REVIEWS GENETICS, 2009, 10 (10) :691-703

[5] DNase I sensitivity QTLs are a major determinant of human expression variation [J].

Degner, Jacob F. ;

Pai, Athma A. ;

Pique-Regi, Roger ;

Veyrieras, Jean-Baptiste ;

Gaffney, Daniel J. ;

Pickrell, Joseph K. ;

De Leon, Sherryl ;

Michelini, Katelyn ;

Lewellen, Noah ;

Crawford, Gregory E. ;

Stephens, Matthew ;

Gilad, Yoav ;

Pritchard, Jonathan K. .

NATURE, 2012, 482 (7385) :390-394

[6] Landscape of transcription in human cells [J].

Djebali, Sarah ;

Davis, Carrie A. ;

Merkel, Angelika ;

Dobin, Alex ;

Lassmann, Timo ;

Mortazavi, Ali ;

Tanzer, Andrea ;

Lagarde, Julien ;

Lin, Wei ;

Schlesinger, Felix ;

Xue, Chenghai ;

Marinov, Georgi K. ;

Khatun, Jainab ;

Williams, Brian A. ;

Zaleski, Chris ;

Rozowsky, Joel ;

Roeder, Maik ;

Kokocinski, Felix ;

Abdelhamid, Rehab F. ;

Alioto, Tyler ;

Antoshechkin, Igor ;

Baer, Michael T. ;

Bar, Nadav S. ;

Batut, Philippe ;

Bell, Kimberly ;

Bell, Ian ;

Chakrabortty, Sudipto ;

Chen, Xian ;

Chrast, Jacqueline ;

Curado, Joao ;

Derrien, Thomas ;

Drenkow, Jorg ;

Dumais, Erica ;

Dumais, Jacqueline ;

Duttagupta, Radha ;

Falconnet, Emilie ;

Fastuca, Meagan ;

Fejes-Toth, Kata ;

Ferreira, Pedro ;

Foissac, Sylvain ;

Fullwood, Melissa J. ;

Gao, Hui ;

Gonzalez, David ;

Gordon, Assaf ;

Gunawardena, Harsha ;

Howald, Cedric ;

Jha, Sonali ;

Johnson, Rory ;

Kapranov, Philipp ;

King, Brandon .

NATURE, 2012, 489 (7414) :101-108

[7] An integrated encyclopedia of DNA elements in the human genome [J].

Dunham, Ian ;

Kundaje, Anshul ;

Aldred, Shelley F. ;

Collins, Patrick J. ;

Davis, CarrieA. ;

Doyle, Francis ;

Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

[8] Roles for MicroRNAs in Conferring Robustness to Biological Processes [J].

Ebert, Margaret S. ;

Sharp, Phillip A. .

CELL, 2012, 149 (03) :515-524

[9] Genetics of gene expression and its effect on disease [J].

Emilsson, Valur ;

Thorleifsson, Gudmar ;

Zhang, Bin ;

Leonardson, Amy S. ;

Zink, Florian ;

Zhu, Jun ;

Carlson, Sonia ;

Helgason, Agnar ;

Walters, G. Bragi ;

Gunnarsdottir, Steinunn ;

Mouy, Magali ;

Steinthorsdottir, Valgerdur ;

Eiriksdottir, Gudrun H. ;

Bjornsdottir, Gyda ;

Reynisdottir, Inga ;

Gudbjartsson, Daniel ;

Helgadottir, Anna ;

Jonasdottir, Aslaug ;

Jonasdottir, Adalbjorg ;

Styrkarsdottir, Unnur ;

Gretarsdottir, Solveig ;

Magnusson, Kristinn P. ;

Stefansson, Hreinn ;

Fossdal, Ragnheidur ;

Kristjansson, Kristleifur ;

Gislason, Hjortur G. ;

Stefansson, Tryggvi ;

Leifsson, Bjorn G. ;

Thorsteinsdottir, Unnur ;

Lamb, John R. ;

Gulcher, Jeffrey R. ;

Reitman, Marc L. ;

Kong, Augustine ;

Schadt, Eric E. ;

Stefansson, Kari .

NATURE, 2008, 452 (7186) :423-U2

[10] Dissecting the regulatory architecture of gene expression QTLs [J].

Gaffney, Daniel J. ;

Veyrieras, Jean-Baptiste ;

Degner, Jacob F. ;

Pique-Regi, Roger ;

Pai, Athma A. ;

Crawford, Gregory E. ;

Stephens, Matthew ;

Gilad, Yoav ;

Pritchard, Jonathan K. .

GENOME BIOLOGY, 2012, 13 (01)

← 1 2 3 4 →