Understanding mechanisms underlying human gene expression variation with RNA sequencing

被引:919
作者
Pickrell, Joseph K. [1 ]
Marioni, John C. [1 ]
Pai, Athma A. [1 ]
Degner, Jacob F. [1 ]
Engelhardt, Barbara E. [2 ]
Nkadori, Everlyne [1 ,3 ]
Veyrieras, Jean-Baptiste [1 ]
Stephens, Matthew [1 ,4 ]
Gilad, Yoav [1 ]
Pritchard, Jonathan K. [1 ,3 ]
机构
[1] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Comp Sci, Chicago, IL 60637 USA
[3] Univ Chicago, Howard Hughes Med Inst, Chicago, IL 60637 USA
[4] Univ Chicago, Dept Stat, Chicago, IL 60637 USA
关键词
GENOME; CELLS; SEQ; CONTRIBUTE; DISCOVERY; VARIANTS;
D O I
10.1038/nature08872
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
Understanding the genetic mechanisms underlying natural variation in gene expression is a central goal of both medical and evolutionary genetics, and studies of expression quantitative trait loci (eQTLs) have become an important tool for achieving this goal(1). Although all eQTL studies so far have assayed messenger RNA levels using expression microarrays, recent advances in RNA sequencing enable the analysis of transcript variation at unprecedented resolution. We sequenced RNA from 69 lymphoblastoid cell lines derived from unrelated Nigerian individuals that have been extensively genotyped by the International HapMap Project(2). By pooling data from all individuals, we generated a map of the transcriptional landscape of these cells, identifying extensive use of unannotated untranslated regions and more than 100 new putative protein-coding exons. Using the genotypes from the HapMap project, we identified more than a thousand genes at which genetic variation influences overall expression levels or splicing. We demonstrate that eQTLs near genes generally act by a mechanism involving allele-specific expression, and that variation that influences the inclusion of an exon is enriched within and near the consensus splice sites. Our results illustrate the power of high-throughput sequencing for the joint analysis of variation in transcription, splicing and allele-specific expression across individuals.
引用
收藏
页码:768 / 772
页数:5
相关论文
共 29 条
[1]   Mapping determinants of human gene expression by regional and genome-wide association [J].
Cheung, VG ;
Spielman, RS ;
Ewens, KG ;
Weber, TM ;
Morley, M ;
Burdick, JT .
NATURE, 2005, 437 (7063) :1365-1369
[2]   Natural variation in human gene expression assessed in lymphoblastoid cells [J].
Cheung, VG ;
Conlin, LK ;
Weber, TM ;
Arcaro, M ;
Jen, KY ;
Morley, M ;
Spielman, RS .
NATURE GENETICS, 2003, 33 (03) :422-425
[3]   Genetic Analysis of Human Traits In Vitro: Drug Response and Gene Expression in Lymphoblastoid Cell Lines [J].
Choy, Edwin ;
Yelensky, Roman ;
Bonakdar, Sasha ;
Plenge, Robert M. ;
Saxena, Richa ;
De Jager, Philip L. ;
Shaw, Stanley Y. ;
Wolfish, Cara S. ;
Slavik, Jacqueline M. ;
Cotsapas, Chris ;
Rivas, Manuel ;
Dermitzakis, Emmanouil T. ;
Cahir-McFarland, Ellen ;
Kieff, Elliott ;
Hafler, David ;
Daly, Mark J. ;
Altshuler, David .
PLOS GENETICS, 2008, 4 (11)
[4]   Stem cell transcriptome profiling via massive-scale mRNA sequencing [J].
Cloonan, Nicole ;
Forrest, Alistair R. R. ;
Kolle, Gabriel ;
Gardiner, Brooke B. A. ;
Faulkner, Geoffrey J. ;
Brown, Mellissa K. ;
Taylor, Darrin F. ;
Steptoe, Anita L. ;
Wani, Shivangi ;
Bethel, Graeme ;
Robertson, Alan J. ;
Perkins, Andrew C. ;
Bruce, Stephen J. ;
Lee, Clarence C. ;
Ranade, Swati S. ;
Peckham, Heather E. ;
Manning, Jonathan M. ;
McKernan, Kevin J. ;
Grimmond, Sean M. .
NATURE METHODS, 2008, 5 (07) :613-619
[5]   Effect of read-mapping biases on detecting allele-specific expression from RNA-sequencing data [J].
Degner, Jacob F. ;
Marioni, John C. ;
Pai, Athma A. ;
Pickrell, Joseph K. ;
Nkadori, Everlyne ;
Gilad, Yoav ;
Pritchard, Jonathan K. .
BIOINFORMATICS, 2009, 25 (24) :3207-3212
[6]   Common polymorphic transcript variation in human disease [J].
Fraser, Hunter B. ;
Xie, Xiaohui .
GENOME RESEARCH, 2009, 19 (04) :567-575
[7]   A second generation human haplotype map of over 3.1 million SNPs [J].
Frazer, Kelly A. ;
Ballinger, Dennis G. ;
Cox, David R. ;
Hinds, David A. ;
Stuve, Laura L. ;
Gibbs, Richard A. ;
Belmont, John W. ;
Boudreau, Andrew ;
Hardenbol, Paul ;
Leal, Suzanne M. ;
Pasternak, Shiran ;
Wheeler, David A. ;
Willis, Thomas D. ;
Yu, Fuli ;
Yang, Huanming ;
Zeng, Changqing ;
Gao, Yang ;
Hu, Haoran ;
Hu, Weitao ;
Li, Chaohua ;
Lin, Wei ;
Liu, Siqi ;
Pan, Hao ;
Tang, Xiaoli ;
Wang, Jian ;
Wang, Wei ;
Yu, Jun ;
Zhang, Bo ;
Zhang, Qingrun ;
Zhao, Hongbin ;
Zhao, Hui ;
Zhou, Jun ;
Gabriel, Stacey B. ;
Barry, Rachel ;
Blumenstiel, Brendan ;
Camargo, Amy ;
Defelice, Matthew ;
Faggart, Maura ;
Goyette, Mary ;
Gupta, Supriya ;
Moore, Jamie ;
Nguyen, Huy ;
Onofrio, Robert C. ;
Parkin, Melissa ;
Roy, Jessica ;
Stahl, Erich ;
Winchester, Ellen ;
Ziaugra, Liuda ;
Altshuler, David ;
Shen, Yan .
NATURE, 2007, 449 (7164) :851-U3
[8]   Global patterns of cis variation in human cells revealed by high-density allelic expression analysis [J].
Ge, Bing ;
Pokholok, Dmitry K. ;
Kwan, Tony ;
Grundberg, Elin ;
Morcos, Lisanne ;
Verlaan, Dominique J. ;
Le, Jennie ;
Koka, Vonda ;
Lam, Kevin C. L. ;
Gagne, Vincent ;
Dias, Joana ;
Hoberman, Rose ;
Montpetit, Alexandre ;
Joly, Marie-Michele ;
Harvey, Edward J. ;
Sinnett, Daniel ;
Beaulieu, Patrick ;
Hamon, Robert ;
Graziani, Alexandru ;
Dewar, Ken ;
Harmsen, Eef ;
Majewski, Jacek ;
Goering, Harald H. H. ;
Naumova, Anna K. ;
Blanchette, Mathieu ;
Gunderson, Kevin L. ;
Pastinen, Tomi .
NATURE GENETICS, 2009, 41 (11) :1216-U78
[9]   Practical Issues in Imputation-Based Association Mapping [J].
Guan, Yongtao ;
Stephens, Matthew .
PLOS GENETICS, 2008, 4 (12)
[10]   A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity [J].
Huang, R. Stephanie ;
Duan, Shiwei ;
Bleibel, Wasim K. ;
Kistner, Emily O. ;
Zhang, Wei ;
Clark, Tyson A. ;
Chen, Tina X. ;
Schweitzer, Anthony C. ;
Blume, John E. ;
Cox, Nancy J. ;
Dolan, M. Eileen .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (23) :9758-9763