Ancient and recent adaptive evolution of primate non-homologous end joining genes.
Ancient and recent adaptive evolution of primate non-homologous end joining genes.
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DOI：
10.1371/journal.pgen.1001169
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发表时间：
2010-10-21
期刊：
影响因子：
4.5
通讯作者：
Sawyer SL
中科院分区：
文献类型：
--
作者：
Demogines A;East AM;Lee JH;Grossman SR;Sabeti PC;Paull TT;Sawyer SL
在人类细胞中，DNA双链断裂主要通过非同源末端连接(NHEJ)途径修复。考虑到它们的关键性质，我们预计NHEJ蛋白在进化上是保守的，随着时间的推移，序列变化相对较小。在这里，我们报告说，虽然这些蛋白质的关键结构域如预期的那样保守，但NHEJ蛋白的序列也被反复的正选择塑造，导致其他蛋白质结构域的序列快速进化。为了描述人类NHEJ途径的分子进化，我们为NHEJ基因生成了大量的猿类灵长类序列数据集。基于密码子的基因进化模型为灵长类进化过程中5个NHEJ基因的反复正选择提供了统计支持：XRCC4、NBS1、Artemis、POLλ和CTIP。使用多信号组合(CMS)测试对人类多态数据的分析表明，XRCC4在现代人中也经历了正选择。XRCC4、NBS1和POLλ都有晶体结构，正选择下的残基只落在这些蛋白质的表面。尽管这些残基是积极选择的，但用Nbs1中一个积极选择的位点的变体进行的生化实验证实，DNA修复和检查点信号传递所需的功能是保守的。然而，作为其感染生命周期的一部分，许多病毒与NHEJ途径的蛋白质相互作用。我们认为，病毒和NHEJ基因之间正在进行的进化军备竞赛可能推动了这些关键基因令人惊讶的快速进化。因为所有细胞都会经历DNA损伤，所以它们也必须有修复DNA的机制。当修复DNA故障的蛋白质出现故障时，通常会导致突变和疾病。基于DNA修复蛋白的基本重要性，DNA修复蛋白有望在进化过程中得到很好的保存，以确保最佳的DNA修复功能。然而，先前对酵母分子进化的全基因组研究发现，非同源末端连接(NHEJ)DNA修复途径是酵母基因组中进化最快的两条途径之一。为了分析这一途径在人类中的进化，我们从我们的灵长类亲属那里产生了大量的NHEJ基因进化序列集。与酵母中的情况类似，这一途径中的几个基因在灵长类基因组和现代人类群体中正在迅速进化。因此，复杂而看似相反的选择力量正在塑造这些重要的DNA修复基因的进化。NHEJ基因在酵母和灵长类动物等不同物种群体中快速进化的发现表明，NHEJ途径受到了系统性的干扰，这一途径对人类健康具有潜在的重要意义。
In human cells, DNA double-strand breaks are repaired primarily by the non-homologous end joining (NHEJ) pathway. Given their critical nature, we expected NHEJ proteins to be evolutionarily conserved, with relatively little sequence change over time. Here, we report that while critical domains of these proteins are conserved as expected, the sequence of NHEJ proteins has also been shaped by recurrent positive selection, leading to rapid sequence evolution in other protein domains. In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes. Codon-based models of gene evolution yielded statistical support for the recurrent positive selection of five NHEJ genes during primate evolution: XRCC4, NBS1, Artemis, POLλ, and CtIP. Analysis of human polymorphism data using the composite of multiple signals (CMS) test revealed that XRCC4 has also been subjected to positive selection in modern humans. Crystal structures are available for XRCC4, Nbs1, and Polλ; and residues under positive selection fall exclusively on the surfaces of these proteins. Despite the positive selection of such residues, biochemical experiments with variants of one positively selected site in Nbs1 confirm that functions necessary for DNA repair and checkpoint signaling have been conserved. However, many viruses interact with the proteins of the NHEJ pathway as part of their infectious lifecycle. We propose that an ongoing evolutionary arms race between viruses and NHEJ genes may be driving the surprisingly rapid evolution of these critical genes. Because all cells experience DNA damage, they must also have mechanisms for repairing DNA. When the proteins that repair DNA malfunction, mutation and disease often result. Based on their fundamental importance, DNA repair proteins would be expected to be well preserved over evolutionary time in order to ensure optimal DNA repair function. However, a previous genome-wide study of molecular evolution in Saccharomyces yeast identified the non-homologous end joining (NHEJ) DNA repair pathway as one of the two most rapidly evolving pathways in the yeast genome. In order to analyze the evolution of this pathway in humans, we have generated large evolutionary sequence sets of NHEJ genes from our primate relatives. Similar to the scenario in yeast, several genes in this pathway are evolving rapidly in primate genomes and in modern human populations. Thus, complex and seemingly opposite selective forces are shaping the evolution of these important DNA repair genes. The finding that NHEJ genes are rapidly evolving in species groups as diverse as yeasts and primates indicates a systematic perturbation of the NHEJ pathway, one that is potentially important to human health.
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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：
1.9
作者：
COCKERHAM, CC;WEIR, BS
通讯作者：
WEIR, BS
影响因子：
5.4
作者：
Evans, JD;Hearing, P
通讯作者：
Hearing, P
影响因子：
3.8
作者：
Garcia-Diaz, M;Bebenek, K;Kunkel, TA
通讯作者：
Kunkel, TA
影响因子：
8
作者：
Bruton, R. K.;Rasti, M.;Grand, R. J. A.
通讯作者：
Grand, R. J. A.