Gene copy-number polymorphism caused by retrotransposition in humans.
Gene copy-number polymorphism caused by retrotransposition in humans.
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DOI：
10.1371/journal.pgen.1003242
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
de Souza SJ
中科院分区：
文献类型：
--
作者：
Schrider DR;Navarro FC;Galante PA;Parmigiani RB;Camargo AA;Hahn MW;de Souza SJ
全基因组测序时代已经揭示了由重复和缺失事件引起的基因拷贝数变化具有重要的进化、功能和表型后果。因此，最近的研究集中在揭示人类和其他物种的自然种群内拷贝数的变化程度。这些研究在人类中发现了大量的拷贝数变异（CNVs），其中许多已被证明具有临床或进化重要性。在大多数情况下，这些研究未能检测到一类重要的基因拷贝数多态性：由反转录转座引起的基因复制，这导致亲本基因的一个新的无内含子拷贝插入基因组中的随机位置。在这里，我们描述了一种利用下一代序列数据来检测由逆转录转座（retroCNVs）引起的基因拷贝数变异的计算方法，我们报告了人类中这些变异的第一个全基因组分析。我们发现，retroCNVs占任何两个人之间的基因拷贝数差异的很大一部分。此外，我们表明，这些变体可能经常导致表达嵌合转录，强调其潜在的新基因功能的进化。通过定位这些重复的插入位点，我们能够表明retroCNVs在最近的人类适应中发挥了重要作用，我们还发现了正选择目前可能正在驱动多个retroCNVs固定的证据。总之，这些发现意味着，retroCNVs是一个特别重要的多态性，和拷贝数变异的未来研究应该寻找这些变异，以阐明其潜在的进化和功能的相关性。最近对人类遗传变异的研究表明，除了单核苷酸多态性不同之外，个体在基因组的许多区域的拷贝数也不同。这些拷贝数变异（CNV）是由复制或缺失事件引起的，通常会影响基因等功能序列。揭示CNV功能影响的努力已经确定了许多增加各种疾病风险的变体，其中一些是适应性的。然而，这些研究大多未能检测到由逆转录转座引起的基因复制，其中mRNA转录物被逆转录并重新插入基因组，产生新的无内含子基因拷贝。在这里，我们描述了一种利用下一代序列数据来准确检测由反转录转座或反转录CNV引起的基因拷贝数变异的方法，并将该方法应用于来自三个不同人类亚群的数百个全基因组序列。我们发现，这些变异占个体之间的基因拷贝数差异的大量，基因反转录转座往往会导致有害和有益的突变。事实上，我们提出的证据表明，这些新的基因重复中的两个可能是适应性的。这些结果表明，retroCNVs是一个特别重要的一类CNV，并应包括在未来的人类拷贝数变异的研究。
The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance. Recent studies of human genetic variation have revealed that, in addition to differing at single nucleotide polymorphisms, individuals differ in copy-number at many regions of the genome. These copy-number variants (CNVs) are caused by duplication or deletion events and often affect functional sequences such as genes. Efforts to reveal the functional impact of CNVs have identified many variants increasing the risk of various disorders, and some that are adaptive. However, these studies mostly fail to detect gene duplications caused by retrotransposition, in which an mRNA transcript is reverse-transcribed and reinserted into the genome, yielding a new intron-less gene copy. Here we describe a method leveraging next-generation sequence data to accurately detect gene copy-number variants caused by retrotransposition, or retroCNVs, and apply this method to hundreds of whole-genome sequences from three different human subpopulations. We find that these variants account for a substantial number of gene copy-number differences between individuals, and that gene retrotransposition may often result in both deleterious and beneficial mutations. Indeed, we present evidence that two of these new gene duplications may be adaptive. These results imply that retroCNVs are an especially important class of CNV and should be included in future studies of human copy-number variation.
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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：
3.7
作者：
Demuth JP;De Bie T;Stajich JE;Cristianini N;Hahn MW
通讯作者：
Hahn MW
影响因子：
3.6
作者：
Cardenas-Navia, L. Isabel;Cruz, Pedro;Samuels, Yardena
通讯作者：
Samuels, Yardena
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE
影响因子：
9.8
作者：
Cario, Holger;Smith, Desiree E. C.;Schwarz, Klaus
通讯作者：
Schwarz, Klaus