Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies.
Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies.
复制标题
DOI：
10.1371/journal.pgen.0010056
复制
发表时间：
2005-10
期刊：
影响因子：
4.5
通讯作者：
Scherer SW
中科院分区：
文献类型：
--
作者：
Feuk L;MacDonald JR;Tang T;Carson AR;Li M;Rao G;Khaja R;Scherer SW
有了黑猩猩基因组序列组装草案，现在就有可能进行全基因组分析，以在亚微观水平上识别黑猩猩和人类之间发生的结构重排。这项研究的目的是调查黑猩猩和人类基因组之间倒置的染色体区域。利用构建人类和黑猩猩基因组组合的网络比对，我们总共确定了1,576个假定的反向定位区域，覆盖了超过154个DNA百万碱基。DNA片段分布在整个基因组中，长度从23个碱基对到62个百万碱基不等。在66个长度超过25kb的倒位中，75%的倒位位于一侧或两侧(通常是无关的)节段性复制。利用聚合酶链式反应和荧光原位杂交，我们实验验证了27个半随机选择区域中的23个(85%)；确认的最大新倒位是位于人类染色体7p14的4.3兆碱基。大猩猩被用作外部群体，为变种赋予祖先地位。然后对所有实验验证的倒位区域进行了针对一组人类样本的分析，发现23个区域中的3个(13%)在人类基因组中是多态的。这些多态倒位包括730kb(7p22)、13kb(7q11)和1kb(16q24)片段，小等位基因频率分别为5%、30%和48%。我们的结果表明，在灵长类基因组进化中，倒位是一个重要的变异来源。在人类中至少发现了三个新的倒位多态，这表明这种类型的结构变异可能是我们基因组中比以前认识到的更常见的特征。黑猩猩是与人类最接近的亲戚，彼此的DNA序列约98%相同。小的DNA序列变化，可能更重要的是更大的染色体结构变化，导致了大约600万年前这两个物种的分化。直到最近，在显微镜下可以看到黑猩猩和人类之间的10个结构差异，其中9个是DNA倒置。通过对基因组序列的计算比较，目前的研究确定了另外1,576个假定的反转事件。其中33个碱基对的大小超过10万个碱基对，29个基因相交，这是进化研究的优先事项。其中23个倒置已被实验证实，其中最大的是人类7号染色体上430万个碱基对。令人惊讶的是，在人类种群中，发现其中3个“倒置”区域的方向不同(在某些情况下，倒置是在黑猩猩身上发现的祖先方向)。这些观察表明，人类基因组仍在结构上进化。此外，由于这种可变的倒置已被证明易于发生染色体的其他(有时是有害的)变化，新数据描绘了潜在的疾病相关基因。
With a draft genome-sequence assembly for the chimpanzee available, it is now possible to perform genome-wide analyses to identify, at a submicroscopic level, structural rearrangements that have occurred between chimpanzees and humans. The goal of this study was to investigate chromosomal regions that are inverted between the chimpanzee and human genomes. Using the net alignments for the builds of the human and chimpanzee genome assemblies, we identified a total of 1,576 putative regions of inverted orientation, covering more than 154 mega-bases of DNA. The DNA segments are distributed throughout the genome and range from 23 base pairs to 62 mega-bases in length. For the 66 inversions more than 25 kilobases (kb) in length, 75% were flanked on one or both sides by (often unrelated) segmental duplications. Using PCR and fluorescence in situ hybridization we experimentally validated 23 of 27 (85%) semi-randomly chosen regions; the largest novel inversion confirmed was 4.3 mega-bases at human Chromosome 7p14. Gorilla was used as an out-group to assign ancestral status to the variants. All experimentally validated inversion regions were then assayed against a panel of human samples and three of the 23 (13%) regions were found to be polymorphic in the human genome. These polymorphic inversions include 730 kb (at 7p22), 13 kb (at 7q11), and 1 kb (at 16q24) fragments with a 5%, 30%, and 48% minor allele frequency, respectively. Our results suggest that inversions are an important source of variation in primate genome evolution. The finding of at least three novel inversion polymorphisms in humans indicates this type of structural variation may be a more common feature of our genome than previously realized. Chimpanzee is the closest relative to humans having DNA sequences about 98% identical to each other. Small DNA sequence changes and probably more importantly, larger structural changes of chromosomes, led to the divergence of the two species some 6 million years ago. Until recently, there were ten structural differences visible under the microscope between chimpanzee and human, and nine of these were inversions of DNA. Through computational comparisons of genome sequences, the current study identifies another 1,576 putative inversion events. Thirty-three of these were larger than 100,000 base pairs in size and 29 intersect genes, prioritizing them for evolutionary studies. Twenty-three of the inversions have been confirmed experimentally with the largest being 4.3 million base pairs in size on human Chromosome 7. Surprisingly, three of the “inverted” regions were found to be variable in their orientation in the human population (in some cases the inversion was in the ancestral orientation found in chimpanzee). These observations indicate the human genome is still evolving in structure. Moreover, since such variable inversions have been shown to predispose to other (sometimes deleterious) changes in chromosomes, the new data delineate potential disease-associated genes.
登录
查看更多内容
影响因子：
12.3
作者：
Bailey JA;Baertsch R;Kent WJ;Haussler D;Eichler EE
通讯作者：
Eichler EE
小鼠基因组中最近的分段和基因重复。
影响因子：
12.3
作者：
Cheung, Joseph;Wilson, Michael D;Zhang, Junjun;Khaja, Razi;MacDonald, Jeffrey R;Heng, Henry H Q;Koop, Ben F;Scherer, Stephen W
通讯作者：
Scherer, Stephen W
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：
5.8
作者：
Kozik, A;Kochetkova, E;Michelmore, R
通讯作者：
Michelmore, R
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C