Splicing and the evolution of proteins in mammals.
Splicing and the evolution of proteins in mammals.
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DOI：
10.1371/journal.pbio.0050014
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发表时间：
2007-02
期刊：
影响因子：
9.8
通讯作者：
Hurst LD
中科院分区：
文献类型：
--
作者：
Parmley JL;Urrutia AO;Potrzebowski L;Kaessmann H;Hurst LD
通常认为蛋白质的进化速度和氨基酸含量是由蛋白质的功能和解剖结构决定的。在这里，我们研究了另一种可能性，即在未加工的RNA中，在内含子-外显子边界附近，指定去除内含子所需的信息（例如，外显子剪接增强子）影响氨基酸使用和蛋白质进化速率。我们发现大多数氨基酸在内含子-外显子边界附近显示出偏斜的使用，并且精氨酸和亮氨酸的2倍和4倍区块的趋势差异表明这是由于在核苷酸水平介导的效应。更具体地，在边界附近优选/避免氨基酸的程度与其在剪接增强子中的富集/缺乏之间存在稳健的关系。正如可以预期的那样，进化速率在内含子-外显子边界附近最低，至少部分是由于剪接增强子，使得内含子-外显子连接处侧翼的结构域平均进化速率低于来自相同基因的外显子中心的一半。相比之下，无内含子逆转录基因的进化速率最高的区域附近的内含子-外显子连接以前居住。内含子-外显子边界附近序列的比例是迄今为止描述的哺乳动物中蛋白质进化速率的较强预测因子之一。我们的结论是，内含子插入后的选择有利于修改附近的内含子-外显子交界处的氨基酸含量，从而使有效的内含子去除，这些变化，然后受到强大的纯化选择，即使非最佳的蛋白质功能。因此，在哺乳动物中存在着一种强大的力量在蛋白质进化中起作用，而这种力量不能直接用蛋白质的生物学来解释。内含子-外显子边界，一旦固定在蛋白质中，被发现受到纯化选择，即使它们不是最佳的蛋白质功能。 我们基因中的大部分DNA实际上并不参与蛋白质的特化。相反，具有蛋白质编码信息（外显子）的位被非编码位（内含子）彼此分开。在基因被翻译成蛋白质之前，这些内含子被移除，外显子被拼接在一起，翻译成蛋白质。虽然关于去除哪些DNA的信息主要在内含子本身中，但内含子-外显子边界附近的部分外显子可以例如作为剪接增强子元件。因此，原则上，外显子的这些部分有两个功能：指定产生的蛋白质的氨基酸和使内含子正确去除。这会对基因的进化产生什么影响？我们发现，附近的内含子-外显子边界，氨基酸的使用偏向于参与剪接控制的核苷酸。此外，基因的这些部分进化得特别慢。事实上，我们估计，一个有许多外显子的基因的进化速度不到没有内含子的基因的一半，这仅仅是因为需要指定在哪里删除内含子。同样，失去内含子的基因在前内含子位置附近进化得特别快。因此，人类蛋白质可能并没有达到最优化的程度，因为它们的序列起着两种相互冲突的作用。
It is often supposed that a protein's rate of evolution and its amino acid content are determined by the function and anatomy of the protein. Here we examine an alternative possibility, namely that the requirement to specify in the unprocessed RNA, in the vicinity of intron–exon boundaries, information necessary for removal of introns (e.g., exonic splice enhancers) affects both amino acid usage and rates of protein evolution. We find that the majority of amino acids show skewed usage near intron–exon boundaries, and that differences in the trends for the 2-fold and 4-fold blocks of both arginine and leucine show this to be owing to effects mediated at the nucleotide level. More specifically, there is a robust relationship between the extent to which an amino acid is preferred/avoided near boundaries and its enrichment/paucity in splice enhancers. As might then be expected, the rate of evolution is lowest near intron–exon boundaries, at least in part owing to splice enhancers, such that domains flanking intron–exon junctions evolve on average at under half the rate of exon centres from the same gene. In contrast, the rate of evolution of intronless retrogenes is highest near the domains where intron–exon junctions previously resided. The proportion of sequence near intron–exon boundaries is one of the stronger predictors of a protein's rate of evolution in mammals yet described. We conclude that after intron insertion selection favours modification of amino acid content near intron–exon junctions, so as to enable efficient intron removal, these changes then being subject to strong purifying selection even if nonoptimal for protein function. Thus there exists a strong force operating on protein evolution in mammals that is not explained directly in terms of the biology of the protein. Intron-exon boundaries, once fixed in proteins, are found to be subject to purifying selection, even if they are not optimal for protein function. Most of the DNA in our genes is actually not involved in the specification of proteins. Rather, the bits with the protein-coding information (exons) are separated from each other by noncoding bits, introns. Before a gene can be translated into protein these introns are removed and the exons are spliced back together to be translated into protein. While information about which DNA to remove is largely in the introns themselves, parts of the exons near the intron–exon boundary can, for example, function as splice enhancer elements. In principle, then, these parts of exons have two functions: to specify the amino acids of the resulting protein and to enable the correct removal of introns. What impact might this have on a gene's evolution? We show that near intron–exon boundaries, amino acid usage is biased towards nucleotides involved in splice control. Moreover, these parts of genes evolve especially slowly. Indeed, we estimate that a gene with many exons would evolve at under half the rate of the same gene with no introns, simply owing to the need to specify where to remove introns. Likewise, genes that have lost their introns evolve especially fast near the former intron's location. Thus, human proteins may not be as optimised as they could be, as their sequence is serving two conflicting roles.
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影响因子：
9.8
作者：
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