来自加拿大多伦多大学细胞与生物分子研究Donnelly中心(Donnelly Center for Cellular and Biomolecular Research)、美国加州大学洛杉矶分校分子生物学研究院、爱荷华州大学等处的研究人员揭示了为什么尽管人类与黑猩猩在基因上只存在大约1%的差异,却在行为、思考和对抗疾病方面有很大的差异。这一研究成果公布在《基因与发育》(Genes and Development)杂志上。
这一由多伦多大学细胞与生物分子中心主导完成的创新性研究比较了人类和黑猩猩大脑,以及心脏组织的样品,获得了对于这些令人费解的谜的新解释,研究人员主要包括多伦多大学教授Benjamin Blencow,以及其研究生John Calarco等人,他们共同努力发现了遗传物质在剪接翻译成蛋白过程中的重要差异。
Blencowe表示,“显然人类与黑猩猩在许多水平上差异极大,但是我们希望了解剪接过程是否在其中扮演了极为重要的角色,决定一些基础性差异”,“我们惊讶的发现,研究中的6-8%的可变剪接存在差异——这是十分大的差异,并且这些表现出剪接差异的基因都与许多重要的事件相关,比如某些疾病的易感性。”
剪接是细胞生物体产生复杂蛋白的一个重要机制,指基因的编码区域参与到蛋白产生的遗传信息中来,可变剪接能够用相同的遗传信息产生多种类型的蛋白,这一新发现揭示可变剪接过程在人类和黑猩猩之间存在巨大差异。
Blencowe认为,这一研究也对于未来人类和黑猩猩疾病的治疗意义重大,“了解我们为什么如此不同对于理解为什么某些疾病只影响一个种群,而不影响另一个种群具有深远的意义。”
原始出处:
Published online before print October 31, 2007, 10.1101/gad.1606907
GENES & DEVELOPMENT 21:2963-2975, 2007
Global analysis of alternative splicing differences between humans and chimpanzees
John A. Calarco1,2,8, Yi Xing3,4,8, Mario Cáceres5,6,8, Joseph P. Calarco1, Xinshu Xiao7, Qun Pan1, Christopher Lee3, Todd M. Preuss5,10, and Benjamin J. Blencowe1,2,9
1 Banting and Best Department of Medical Research, University of Toronto, Terrence Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario M5S 3E1, Canada; 2 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; 3 Molecular Biology Institute, Center for Genomics and Proteomics, Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA; 4 Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine and Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, Iowa, 52242, USA; 5 Division of Neuroscience and Center for Behavioral Neuroscience, Yerkes National Primate Research Center, and Department of Pathology, Emory University, Atlanta, Georgia 30329, USA; 6 Genes and Disease Program, Center for Genomic Regulation (CRG-UPF), 08003 Barcelona, Spain; 7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Alternative splicing is a powerful mechanism affording extensive proteomic and regulatory diversity from a limited repertoire of genes. However, the extent to which alternative splicing has contributed to the evolution of primate species-specific characteristics has not been assessed previously. Using comparative genomics and quantitative microarray profiling, we performed the first global analysis of alternative splicing differences between humans and chimpanzees. Surprisingly, 6%–8% of profiled orthologous exons display pronounced splicing level differences in the corresponding tissues from the two species. Little overlap is observed between the genes associated with alternative splicing differences and the genes that display steady-state transcript level differences, indicating that these layers of regulation have evolved rapidly to affect distinct subsets of genes in humans and chimpanzees. The alternative splicing differences we detected are predicted to affect diverse functions including gene expression, signal transduction, cell death, immune defense, and susceptibility to diseases. Differences in expression at the protein level of the major splice variant of Glutathione S-transferase omega-2 (GSTO2), which functions in the protection against oxidative stress and is associated with human aging-related diseases, suggests that this enzyme is less active in human cells compared with chimpanzee cells. The results of this study thus support an important role for alternative splicing in establishing differences between humans and chimpanzees.
[Keywords: Alternative splicing; gene regulation; microarray profiling; primate evolution]]
Received August 20, 2007; revised version accepted September 18, 2007.