The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing.
The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing.
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DOI：
10.7554/elife.05198
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发表时间：
2015-01-08
期刊：
影响因子：
7.7
通讯作者：
Eisenberg E
中科院分区：
文献类型：
--
作者：
Alon S;Garrett SC;Levanon EY;Olson S;Graveley BR;Rosenthal JJ;Eisenberg E
腺苷脱氨基的RNA编辑改变了基因组蓝图中的遗传信息。当它重新编码mRNAs时，它给生物体提供了表达不同的、功能不同的蛋白质亚型的选择。所有的真核生物，从蛇类到人类，都表达RNA编辑酶。然而，转录组范围的屏幕只发现了大约25个转录本，其中包含哺乳动物中保守的重新编码RNA编辑位点和果蝇中的数百个重新编码位点。这些对少数已建立模型的研究导致了一个普遍的假设，即通过RNA编辑进行重新编码的情况极其罕见。在这里，我们使用了一种新的生物信息学方法，并进行了广泛的验证，以表明鱿鱼Doryteuthis pealeii通过RNA编辑重新编码蛋白质的程度达到了前所未有的程度。我们确定了神经系统中的57,108个重新编码位点，影响了所研究的大多数蛋白质。重新编码是组织依赖的，并且丰富了具有神经元和细胞骨架功能的基因，这表明它在大脑生理学中发挥着重要作用。活细胞要产生蛋白质，首先必须‘转录’在其http://dx.doi.org/10.7554/eLife.05198.001中发现的遗传密码，以产生相应的信使核糖核酸分子。DNA和RNA都是由称为核苷酸的较小分子组成的，这些核苷酸连接成长链；DNA和RNA中的信息都包含在这些分子的序列中。编码蛋白质的信使核糖核酸以三个为一组进行翻译，这些核苷酸三联体中的大多数指示将特定的氨基酸添加到新形成的蛋白质中。DNA序列被认为与所产生的蛋白质中的氨基酸序列完全一致。然而，现在已经知道，被称为RNA编辑的过程可以在从DNA转录后改变信使核糖核酸分子的核苷酸序列。一种这样的编辑过程称为A-to-I编辑，它改变‘A’核苷酸，使翻译机器将其读作‘G’核苷酸。在某些情况下，但不是所有的情况下，这一事件会改变，或‘重新编码’，由这段mRNA编码的氨基酸，这可能会改变蛋白质的行为。这种从单个DNA序列产生一系列蛋白质的能力可以帮助生物体进化出新的特征。到目前为止，只在少数几个被调查的物种中发现了氨基酸重新编码的证据，程度非常有限。有一些证据表明，在鱿鱼和章鱼中，重新编码可能会更频繁地发生，并改变更多的蛋白质。然而，这一点无法得到证实，因为这些物种的基因组还没有测序，这些序列需要使用现有技术来研究RNA重新编码。Alon等人。现在已经开发出一种新的方法，可以在基因组尚未测序的有机体中识别重新编码的位置。使用这项技术--将mRNA序列与转录它们的DNA序列进行比较--检查鱿鱼神经系统，发现了超过57000个重新编码位点，其中A核苷酸被修改为G核苷酸，从而改变了编码的氨基酸。许多已识别的信使核糖核酸分子在不止一个位置被重新编码，其中比预期多得多的分子改变了从它们翻译的蛋白质的氨基酸序列。Alon等人。因此，我们认为，RNA编辑可能在鱿鱼神经系统的进化过程中起到了至关重要的作用，并认为重新编码应该被认为是鱿鱼制造蛋白质过程中的正常部分。DOI：http://dx.doi.org/10.7554/eLife.05198.002
RNA editing by adenosine deamination alters genetic information from the genomic blueprint. When it recodes mRNAs, it gives organisms the option to express diverse, functionally distinct, protein isoforms. All eumetazoans, from cnidarians to humans, express RNA editing enzymes. However, transcriptome-wide screens have only uncovered about 25 transcripts harboring conserved recoding RNA editing sites in mammals and several hundred recoding sites in Drosophila. These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare. Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent. We identify 57,108 recoding sites in the nervous system, affecting the majority of the proteins studied. Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology. DOI: http://dx.doi.org/10.7554/eLife.05198.001 For living cells to create a protein, a genetic code found in its DNA must first be ‘transcribed’ to create a corresponding molecule of messenger RNA (mRNA). DNA and RNA are both made from smaller molecules called nucleotides that are linked together into long chains; the information in both DNA and RNA is contained in the sequence of these molecules. The mRNA nucleotides coding for proteins are ‘translated’ in groups of three, and most of these nucleotide triplets instruct for a specific amino acid to be added to the newly forming protein. DNA sequences were thought to exactly correspond with the sequence of amino acids in the resulting protein. However, it is now known that processes called RNA editing can change the nucleotide sequence of the mRNA molecules after they have been transcribed from the DNA. One such editing process, called A-to-I editing, alters the ‘A’ nucleotide so that the translation machinery reads it as a ‘G’ nucleotide instead. In some—but not all—cases, this event will change, or ‘recode’, the amino acid encoded by this stretch of mRNA, which may change how the protein behaves. This ability to create a range of proteins from a single DNA sequence could help organisms to evolve new traits. Evidence of amino acid recoding has only been found to a very limited extent in the few species investigated so far. There has been some evidence that suggests that recoding might occur more often, and alter more proteins, in squids and octopuses. However, this could not be confirmed as the genomes of these species have not been sequenced, and these sequences were required to investigate RNA recoding using existing techniques. Alon et al. have now developed a new approach that allows the recoding sites to be identified in organisms whose genomes have not been sequenced. Using this technique—which compares mRNA sequences with the DNA sequence they have been transcribed from—to examine the squid nervous system revealed over 57,000 recoding sites where an ‘A’ nucleotide had been modified to ‘G’ and thereby changed the coded amino acid. Many of the identified mRNA molecules had been recoded in more than one place, and many more of these than expected changed the amino acid sequence of the protein translated from them. Alon et al. therefore suggest that RNA editing may have been crucial in the evolution of the squid's nervous system, and suggest that recoding should be considered a normal part of the process used by squids to make proteins. DOI: http://dx.doi.org/10.7554/eLife.05198.002