Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay.
Noisy splicing, more than expression regulation, explains why some exons are subject to nonsense-mediated mRNA decay.
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嘈杂的剪接，不仅仅是表达调节，解释了为什么一些外显子会受到无义介导的 mRNA 衰变的影响
DOI：
10.1186/1741-7007-7-23
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发表时间：
2009-05-14
期刊：
影响因子：
5.4
通讯作者：
Hurst LD
中科院分区：
文献类型：
--
作者：
Zhang Z;Xin D;Wang P;Zhou L;Hu L;Kong X;Hurst LD
无义介导的衰变是一种通过过早终止密码子降解 mRNA 的机制。有些外显子在固定时具有过早终止密码子，这是自相矛盾的：如果只是为了被破坏，为什么要制作转录本呢？一种模型假设剪接本质上是有噪声的，并且虚假转录本很常见。在常规生成的不需要的转录物中提前终止密码子的进化可以成为防止昂贵翻译的一种手段。或者，无义介导的衰变可以在某些条件下受到调节，因此提前终止密码子的存在可以成为上调无义介导的衰变被抑制时所需转录本的一种手段。为了解决这个问题，我们研究了人类和小鼠中假定的无意义介导的衰变目标的特性。我们从一组注释良好的蛋白质编码基因开始，发现 2% 到 4% 的基因可能会受到无义介导的衰变，并且过早终止密码子既不反映罕见突变，也不反映测序假象。几条证据表明，噪声剪接模型具有相当大的相关性：1）在无义介导的衰变转录本中独特发现的外显子（无义介导的衰变特异性外显子）往往是新创建的； 2）夹杂程度低； 3）长的往往不是三的倍数； 4) 属于具有多个剪接亚型的基因的情况比预期更多； 5）这些基因在任何功能类别中都没有明显富集，也没有在其他物种中作为无义介导的衰变候选者而保守。然而，可以发现远距离直系同源外显子的无义介导的衰变特异性外显子往往处于纯化选择之下，这与调控模型一致。我们的结论是，对于最近进化的外显子，噪声剪接模型是对其特性的更好解释，而对于古代外显子，无义介导的衰变调节基因表达是一个可行的解释。
Nonsense-mediated decay is a mechanism that degrades mRNAs with a premature termination codon. That some exons have premature termination codons at fixation is paradoxical: why make a transcript if it is only to be destroyed? One model supposes that splicing is inherently noisy and spurious transcripts are common. The evolution of a premature termination codon in a regularly made unwanted transcript can be a means to prevent costly translation. Alternatively, nonsense-mediated decay can be regulated under certain conditions so the presence of a premature termination codon can be a means to up-regulate transcripts needed when nonsense-mediated decay is suppressed. To resolve this issue we examined the properties of putative nonsense-mediated decay targets in humans and mice. We started with a well-annotated set of protein coding genes and found that 2 to 4% of genes are probably subject to nonsense-mediated decay, and that the premature termination codon reflects neither rare mutations nor sequencing artefacts. Several lines of evidence suggested that the noisy splicing model has considerable relevance: 1) exons that are uniquely found in nonsense-mediated decay transcripts (nonsense-mediated decay-specific exons) tend to be newly created; 2) have low-inclusion level; 3) tend not to be a multiple of three long; 4) belong to genes with multiple splice isoforms more often than expected; and 5) these genes are not obviously enriched for any functional class nor conserved as nonsense-mediated decay candidates in other species. However, nonsense-mediated decay-specific exons for which distant orthologous exons can be found tend to have been under purifying selection, consistent with the regulation model. We conclude that for recently evolved exons the noisy splicing model is the better explanation of their properties, while for ancient exons the nonsense-mediated decay regulated gene expression is a viable explanation.
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4.3
作者：
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通讯作者：
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影响因子：
5.8
作者：
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作者：
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影响因子：
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作者：
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Izaurralde, Elisa
DOI：
10.1073/pnas.0506139102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Baek, D;Green, P
通讯作者：
Green, P