Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12174-9. doi: 10.1073/pnas.1006183107. Epub 2010 Jun 21.
Human and chimpanzee genomes are almost identical, yet humans express higher brain capabilities. Deciphering the basis for this superiority is a long sought-after challenge. Adenosine-to-inosine (A-to-I) RNA editing is a widespread modification of the transcriptome. The editing level in humans is significantly higher compared with nonprimates, due to exceptional editing within the primate-specific Alu sequences, but the global editing level of nonhuman primates has not been studied so far. Here we report the sequencing of transcribed Alu sequences in humans, chimpanzees, and rhesus monkeys. We found that, on average, the editing level in the transcripts analyzed is higher in human brain compared with nonhuman primates, even where the genomic Alu structure is unmodified. Correlated editing is observed for pairs and triplets of specific adenosines along the Alu sequences. Moreover, new editable species-specific Alu insertions, subsequent to the human-chimpanzee split, are significantly enriched in genes related to neuronal functions and neurological diseases. The enhanced editing level in the human brain and the association with neuronal functions both hint at the possible contribution of A-to-I editing to the development of higher brain function. We show here that combinatorial editing is the most significant contributor to the transcriptome repertoire and suggest that Alu editing adapted by natural selection may therefore serve as an alternate information mechanism based on the binary A/I code.
人类和黑猩猩的基因组几乎完全相同，但人类却表现出更高的大脑能力。破解这种优势的基础是一个长期以来备受关注的挑战。腺苷到肌苷（A-to-I）RNA 编辑是转录组的一种广泛修饰。由于灵长类特有的 Alu 序列中的特殊编辑，人类的编辑水平明显高于非灵长类动物，但目前尚未研究非灵长类动物的整体编辑水平。在这里，我们报告了人类、黑猩猩和恒河猴转录 Alu 序列的测序结果。我们发现，在分析的转录本中，人类大脑的编辑水平平均高于非灵长类动物，即使基因组 Alu 结构没有改变。在 Alu 序列中，特定腺苷的碱基对和三联体都观察到相关的编辑。此外，在人类和黑猩猩分化之后，新的可编辑的物种特异性 Alu 插入物在与神经元功能和神经疾病相关的基因中显著富集。人类大脑中增强的编辑水平以及与神经元功能的关联都暗示了 A-to-I 编辑可能对高级大脑功能的发展做出了贡献。我们在这里表明，组合编辑是转录组库中最重要的贡献者，并表明自然选择适应的 Alu 编辑可能因此成为基于二元 A/I 代码的替代信息机制。
