A human-specific de novo protein-coding gene associated with human brain functions.
A human-specific de novo protein-coding gene associated with human brain functions.
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DOI：
10.1371/journal.pcbi.1000734
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发表时间：
2010-03-26
影响因子：
4.3
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Li CY;Zhang Y;Wang Z;Zhang Y;Cao C;Zhang PW;Lu SJ;Li XM;Yu Q;Zheng X;Du Q;Uhl GR;Liu QR;Wei L
为了了解是否有任何人类特异性的新基因可能与人脑功能相关，我们通过计算筛选了通过全基因组关联研究和尼古丁成瘾连锁分析确定的遗传易感因素，并发现了一个人类特异性的从头蛋白编码基因FLJ33706（替代基因符号C20orf203）。跨物种分析揭示了该基因如何起源于非编码DNA序列的有趣进化路径：插入重复元件，特别是Alu，有助于在通向人类和黑猩猩的分支上形成第一个编码外显子和六个标准剪接点，并且在人类谱系中的两个后续替换逃脱了两个终止密码子，并创建了一个194个氨基酸的开放阅读框架。我们通过实验验证了FLJ33706在脑中的mRNA和蛋白表达。在多种组织中的实时PCR表明FLJ33706在脑中表达最丰富。人类多态性数据表明，FLJ33706编码的蛋白质纯化选择。一种专门设计的抗体检测了它在人类皮层、小脑和中脑的蛋白表达。在正常人脑皮质中的免疫组织化学研究揭示FLJ33706蛋白在神经元中的定位。FLJ33706在阿尔茨海默氏症的大脑样本中表达升高，表明这种新基因在阿尔茨海默氏症的人类特异性发病机制中的作用。FLJ33706提供了迄今为止最强有力的证据，证明人类特异性从头基因可以具有蛋白质编码潜力和差异蛋白质表达，并参与人脑功能。几十年来，基因复制、逆转录和基因融合被认为是增加基因数量的主要途径。所有这些都涉及"母亲"基因作为新基因的"基石"。然而，最近发现的几个“无母”基因挑战了这一观点，因为一些蛋白质可能是从祖先的非编码DNA中重新出现的。在人类与黑猩猩分化之后，是否有这样的基因出现在人类身上？如果是的话，这些基因可能有助于理解是什么让我们成为人类。在这里，我们报告了第一个实验验证的情况下，人类特异性蛋白质编码基因，FLJ33706（替代基因符号C20orf203），起源从头以来的分歧，人类和黑猩猩。FLJ33706是通过插入重复元件，特别是Alu序列形成的，这有助于形成第一个编码外显子和六个标准剪接点，然后是两个人类特异性取代，逃避终止密码子。FLJ33706基因的功能性蛋白质编码特征得到了群体遗传学、转录组分析、蛋白质印迹和免疫组织化学分析的支持。数据表明FLJ33706可能与尼古丁成瘾和阿尔茨海默病有关。FLJ33706提供了迄今为止最有力的证据，证明人类特异性从头基因可以具有蛋白质编码潜力，并参与人类大脑功能。
To understand whether any human-specific new genes may be associated with human brain functions, we computationally screened the genetic vulnerable factors identified through Genome-Wide Association Studies and linkage analyses of nicotine addiction and found one human-specific de novo protein-coding gene, FLJ33706 (alternative gene symbol C20orf203). Cross-species analysis revealed interesting evolutionary paths of how this gene had originated from noncoding DNA sequences: insertion of repeat elements especially Alu contributed to the formation of the first coding exon and six standard splice junctions on the branch leading to humans and chimpanzees, and two subsequent substitutions in the human lineage escaped two stop codons and created an open reading frame of 194 amino acids. We experimentally verified FLJ33706's mRNA and protein expression in the brain. Real-Time PCR in multiple tissues demonstrated that FLJ33706 was most abundantly expressed in brain. Human polymorphism data suggested that FLJ33706 encodes a protein under purifying selection. A specifically designed antibody detected its protein expression across human cortex, cerebellum and midbrain. Immunohistochemistry study in normal human brain cortex revealed the localization of FLJ33706 protein in neurons. Elevated expressions of FLJ33706 were detected in Alzheimer's brain samples, suggesting the role of this novel gene in human-specific pathogenesis of Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and differential protein expression, and be involved in human brain functions. For decades, gene duplication, retrotranspositions and gene fusions were believed to be major ways to increase gene number. All involve “mother” genes as the “building blocks” for new genes. However, several recently identified “motherless” genes challenged the idea in that some proteins might have emerged de novo from ancestral non-coding DNAs. Did any such genes emerge in human after the divergence from chimpanzee? If yes, such genes might help understand what makes us human. Here we report the first experimentally verified case of a human-specific protein-coding gene, FLJ33706 (alternative gene symbol C20orf203), that originated de novo since the divergence of human and chimpanzee. FLJ33706 was formed by the insertion of repeat elements, especially Alu sequences, that contributed to the formation of the first coding exon and six standard splice junctions, followed by two human-specific substitutions that escaped stop codons. The functional protein-coding features of the FLJ33706 gene are supported by population genetics, transcriptome profiling, Western-blot and immunohistochemistry assays. Data suggest that FLJ33706 may be involved in nicotine addiction and Alzheimer's disease. FLJ33706 provided the strongest evidence so far that human-specific de novo genes can have protein-coding potential and be involved in human brain functions.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1002/ajmg.b.30109
发表时间：
2005-04-05
影响因子：
2.8
作者：
Liu, QR;Walther, D;Uhl, GR
通讯作者：
Uhl, GR
影响因子：
3.3
作者：
Begun, David J.;Lindfors, Heather A.;Jones, Corbin D.
通讯作者：
Jones, Corbin D.
影响因子：
7
作者：
Knowles, David G.;McLysaght, Aoife
通讯作者：
McLysaght, Aoife
DOI：
10.1073/pnas.0509809103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Levine, Mia T.;Jones, Corbin D.;Begun, David J.
通讯作者：
Begun, David J.