Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing
Sequence conservation, relative isoform frequencies, and nonsense-mediated decay in evolutionarily conserved alternative splicing
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DOI：
10.1073/pnas.0506139102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Green, P
中科院分区：
文献类型：
--
作者：
Baek, D;Green, P
对表达序列标签数据集的研究揭示了人类基因的大量剪接变体，但区分功能重要的变体与异常剪接、澄清替代功能的性质以及理解调节剪接选择的信号仍然具有挑战性。为了帮助解决这些问题，我们构建并分析了1，478个外显子跳跃选择性剪接（AS）变体的大型数据集，这些变体在人类和小鼠中进化上保守。在大约五分之一的情况下，一个亚型出现无义介导的mRNA衰变（NMD），支持AS的主要作用是调节基因表达的观点;四分之一的NMD诱导病例涉及保守的外显子，其明显的唯一目的是介导破坏的消息时，包括。我们探索可能与剪接调控相关的序列保守性，部分使用序列中保守信息总量的测量，并发现AS外显子内观察到的保守性增加主要影响同义位点，这表明调控信号显着限制同义置换率。我们发现，包含异构体相对于排斥异构体的频率较低，往往与较弱的剪接位点信号，较小的外显子大小，较高的内含子序列保守性，并提供证据表明，所有这些因素都在选择控制相对异构体频率。AS的一些保守的情况下出现代表异常剪接事件，偶然发生在这两个物种，我们开发了一个非参数似然方法来识别这些。
Studies of expressed sequence tag data sets have revealed large numbers of splicing variants for human genes, but it remains challenging to distinguish functionally important variants from aberrant splicing, clarify the nature of the alternative functions, and understand the signals that regulate splicing choices. To help address these issues, we have constructed and analyzed a large data set of 1,478 exon-skipping alternative splicing (AS) variants evolutionarily conserved in human and mouse. In about one-fifth of cases, one isoform appears subject to nonsense-mediated mRNA decay (NMD), supporting the idea that a major role of AS is to regulate gene expression; one-quarter of these NMD-inducing cases involve a conserved exon whose apparent sole purpose is to mediate destruction of the message when included. We explore sequence conservation likely related to splicing regulation, using in part a measure of the overall amount of conserved information in a sequence, and find that the increased conservation that has been observed within AS exons primarily affects synonymous sites, suggesting that regulatory signals significantly constrain synonymous substitution rates. We show that a lower frequency of the inclusion isoform relative to the exclusion isoform tends to be associated with weaker splice site signals, smaller exon size, and higher intronic sequence conservation, and provide evidence that all of these factors are under selection to control relative isoform frequencies. Some conserved instances of AS appear to represent aberrant splicing events that by chance have occurred in both species, and we develop a nonparametric likelihood approach to identify these.