The contribution of RNA decay quantitative trait loci to inter-individual variation in steady-state gene expression levels.
The contribution of RNA decay quantitative trait loci to inter-individual variation in steady-state gene expression levels.
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DOI：
10.1371/journal.pgen.1003000
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Gilad Y
中科院分区：
文献类型：
--
作者：
Pai AA;Cain CE;Mizrahi-Man O;De Leon S;Lewellen N;Veyrieras JB;Degner JF;Gaffney DJ;Pickrell JK;Stephens M;Pritchard JK;Gilad Y
最近的基因表达QTL（eQTL）定位研究提供了相当深入的了解个体间的调控变异的遗传基础。然而，迄今为止，所有eQTL研究的局限性，其中使用的稳态基因表达水平的测量，是无法直接区分转录和衰减率的变化。为了解决这一差距，我们进行了一项全基因组研究，研究个体间基因特异性mRNA衰减率的变化。使用时程研究设计，我们估计了70个Yoruban HapMap淋巴母细胞样细胞系（LCL）中超过16，000个基因的mRNA衰减率，其中广泛的基因分型数据可用。考虑到基因间的mRNA衰减率，我们发现：（i）正如预期的那样，高表达的基因通常与较低的mRNA衰减率相关，（ii）具有快速mRNA衰减率的基因富含miRNA和RNA结合蛋白的推定结合位点，（iii）具有相似功能作用的基因往往表现出相关的mRNA衰减率。关注个体间mRNA衰减的变化，我们估计稳态表达水平与10%基因的衰减率变化显著相关。有些反直觉的是，对于这些基因中的大约一半，较高的表达与较快的衰减速率相关，这可能是由于mRNA衰减与参与快速细胞反应的基因中的转录过程的耦合。最后，我们使用这些数据来绘制与个体间mRNA衰减率变化特别相关的遗传变异。我们发现了195个这样的基因座，我们将其命名为RNA衰变数量性状基因座（“rdQTL”）。所有观察到的rdQTL都位于调控基因附近，因此被认为是顺式作用。通过分析已知的稳态eQTL的背景下，我们的数据，我们估计，相当大一部分的eQTL与mRNA衰减率的个体间变异。最近对人类功能遗传变异的研究已经确定了许多与基因表达水平变异相关的基因座，称为表达数量性状基因座（eQTL）。然而，这些位点影响基因表达的机制在很大程度上仍然是未知的。具体来说，由于大多数研究依赖于稳态基因表达水平的测量，他们无法区分转录或衰变相关过程的相对影响。为了解决这一差距，我们研究了mRNA衰减过程对人类淋巴母细胞系中超过16，000个基因的稳态基因表达水平的具体影响。通过表征衰减率在70个人，我们表明，稳态表达水平显着影响衰减率的变化为10%的基因。然而，对于这些基因中的大约一半，我们发现具有较高表达水平的个体也具有更快的衰减速率。这种模式指出了转录和衰变过程之间的非简单机制相互作用，特别是对于参与快速细胞反应的基因。最后，我们确定了195个与基因表达变异和mRNA衰减率变异显著相关的遗传变异。利用这些数据，我们估计相当一部分eQTL与mRNA衰减速率的个体间变异相关。
Recent gene expression QTL (eQTL) mapping studies have provided considerable insight into the genetic basis for inter-individual regulatory variation. However, a limitation of all eQTL studies to date, which have used measurements of steady-state gene expression levels, is the inability to directly distinguish between variation in transcription and decay rates. To address this gap, we performed a genome-wide study of variation in gene-specific mRNA decay rates across individuals. Using a time-course study design, we estimated mRNA decay rates for over 16,000 genes in 70 Yoruban HapMap lymphoblastoid cell lines (LCLs), for which extensive genotyping data are available. Considering mRNA decay rates across genes, we found that: (i) as expected, highly expressed genes are generally associated with lower mRNA decay rates, (ii) genes with rapid mRNA decay rates are enriched with putative binding sites for miRNA and RNA binding proteins, and (iii) genes with similar functional roles tend to exhibit correlated rates of mRNA decay. Focusing on variation in mRNA decay across individuals, we estimate that steady-state expression levels are significantly correlated with variation in decay rates in 10% of genes. Somewhat counter-intuitively, for about half of these genes, higher expression is associated with faster decay rates, possibly due to a coupling of mRNA decay with transcriptional processes in genes involved in rapid cellular responses. Finally, we used these data to map genetic variation that is specifically associated with variation in mRNA decay rates across individuals. We found 195 such loci, which we named RNA decay quantitative trait loci (“rdQTLs”). All the observed rdQTLs are located near the regulated genes and therefore are assumed to act in cis. By analyzing our data within the context of known steady-state eQTLs, we estimate that a substantial fraction of eQTLs are associated with inter-individual variation in mRNA decay rates. Recent studies of functional genetic variation in humans have identified numerous loci that are associated with variation in gene expression levels, called expression quantitative trait loci (eQTLs). The mechanisms by which these loci affect gene expression, however, are still largely unknown. Specifically, since most studies rely on measures of steady-state gene expression levels, they are unable to distinguish between the relative influences of either transcriptional- or decay-related processes. To address this gap, we examined the specific impact of mRNA decay processes on steady-state gene expression levels for over 16,000 genes in human lymphoblastoid cell lines. By characterizing decay rates in 70 individuals, we show that steady-state expression levels are significantly influenced by variation in decay rates for 10% of genes. Yet, for roughly half of these genes, we find that individuals with higher expression levels also have faster decay rates. This pattern points to a non-simple mechanistic interplay between transcriptional and decay processes, especially for genes involved in rapid cellular responses. Finally, we identify 195 genetic variants that are significantly associated with both gene expression variation and variation in mRNA decay rates. Using these data, we estimate that that a substantial fraction of eQTLs are associated with inter-individual variation in mRNA decay rates.
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影响因子：
64.8
作者：
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;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
DOI：
10.1073/pnas.112318199
发表时间：
2002-07-23
影响因子：
11.1
作者：
Bernstein, JA;Khodursky, AB;Cohen, SN
通讯作者：
Cohen, SN
影响因子：
16
作者：
Elemento, Olivier;Slonim, Noam;Tavazoie, Saeed
通讯作者：
Tavazoie, Saeed
DOI：
10.2217/fon.10.11
发表时间：
2010-04
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Flavin R;Peluso S;Nguyen PL;Loda M
通讯作者：
Loda M