Institute of Experimental Pathology (ZMBE), University of Münster, Münster, Germany.
Biochimie. 2011 Nov;93(11):1928-34. doi: 10.1016/j.biochi.2011.07.014. Epub 2011 Jul 26.
Protein-coding genes are composed of exons and introns flanked by untranslated regions. Before the mRNA of a gene can be translated into protein, the splicing machinery removes all the intronic regions and joins the protein-coding exons together. Exonization is a process, whereby genes acquire new exons from non-protein-coding, primarily intronic, DNA sequences. Genomic insertions or point mutations within DNA sequences often generate alternative splice sites, causing the splicing system to include new sequences as exons or to elongate existing exons. Because the alternative splice sites are not as efficient as the originals the new variants usually constitute a minor fraction of mature mRNAs. While the prevailing original splice variant maintains functionality, the additional sequence, free from selection pressure, evolves a new function or eventually vanishes. If the new splice variant is advantageous, selection might operate to optimize the new splice sites and consequently increase the proportion of the alternative splice variant. In some instances, the original splice variant is completely replaced by constitutive splicing of the new form. Because of the fortuitous presence of internal splice site-like structures within their sequences, portions of transposed elements frequently serve as modules of exonization. Their recruitment requires a long and versatile optimization process involving multiple changes over a time span of millions, even hundreds of millions, of years. Comparisons of corresponding genes and mRNAs in phylogenetically related species enables one to chronologically reconstruct such changes, from ancient ancestors to living species, in a stepwise manner. We will review this process using three different exemplary cases: (1) the evolution of a constitutively spliced mammalian-wide repeat (MIR), (2) the evolution of an alternative exon 1 from an alternative 5'-extended primary transcript containing an Alu element, and (3) a rare case of the stepwise exoniztion of an Alu element-derived sequence mediated by A-to-I RNA editing.
蛋白质编码基因由侧翼为非翻译区的外显子和内含子组成。在基因的 mRNA 可以被翻译成蛋白质之前，剪接机制会切除所有内含子区域，并将蛋白质编码外显子连接在一起。外显子化是一个过程，通过这个过程，基因从非编码蛋白质的主要是内含子的 DNA 序列中获得新的外显子。DNA 序列中的基因组插入或点突变经常产生替代剪接位点，导致剪接系统将新序列包含为外显子或延长现有外显子。由于替代剪接位点不如原始剪接位点有效，新变体通常构成成熟 mRNA 的一小部分。虽然原始剪接变体仍然保持功能，但额外的序列不受选择压力的影响，从而获得新的功能或最终消失。如果新的剪接变体有利，选择可能会作用于优化新的剪接位点，从而增加替代剪接变体的比例。在某些情况下，原始剪接变体完全被新形式的组成性剪接所取代。由于转座元件序列中存在内部剪接位点样结构，它们的一部分经常作为外显子化的模块。它们的招募需要一个长期而灵活的优化过程，涉及在数百万年甚至数亿年的时间跨度内发生多次变化。比较系统发育相关物种中的相应基因和 mRNA，可以按时间顺序从古代祖先到现存物种逐步重建这些变化。我们将使用三个不同的示例案例来回顾这个过程：（1）组成性剪接哺乳动物广泛重复（MIR）的进化；（2）来自含有 Alu 元件的替代 5'-延伸初级转录本的替代外显子 1 的进化；（3）通过 A-to-I RNA 编辑介导的 Alu 元件衍生序列的罕见逐步外显子化。
