Gal-Mark Nurit, Schwartz Schraga, Ast Gil
Department of Human Genetics and Molecular Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
Nucleic Acids Res. 2008 Apr;36(6):2012-23. doi: 10.1093/nar/gkn024. Epub 2008 Feb 14.
Alus, primate-specific retroelements, are the most abundant repetitive elements in the human genome. They are composed of two related but distinct monomers, left and right arms. Intronic Alu elements may acquire mutations that generate functional splice sites, a process called exonization. Most exonizations occur in right arms of antisense Alu elements, and are alternatively spliced. Here we show that without the left arm, exonization of the right arm shifts from alternative to constitutive splicing. This eliminates the evolutionary conserved isoform and may thus be selected against. We further show that insertion of the left arm downstream of a constitutively spliced non-Alu exon shifts splicing from constitutive to alternative. Although the two arms are highly similar, the left arm is characterized by weaker splicing signals and lower exonic splicing regulatory (ESR) densities. Mutations that improve these potential splice signals activate exonization and shift splicing from the right to the left arm. Collaboration between two or more putative splice signals renders the intronic left arm with a pseudo-exon function. Thus, the dimeric form of the Alu element fortuitously provides it with an evolutionary advantage, allowing enrichment of the primate transcriptome without compromising its original repertoire.
Alu元件是灵长类特有的逆转录元件，是人类基因组中最丰富的重复元件。它们由两个相关但不同的单体，即左臂和右臂组成。内含子Alu元件可能获得产生功能性剪接位点的突变，这一过程称为外显子化。大多数外显子化发生在反义Alu元件的右臂上，并且是可变剪接的。在这里我们表明，没有左臂时，右臂的外显子化从可变剪接转变为组成型剪接。这消除了进化保守的异构体，因此可能会被选择淘汰。我们进一步表明，在组成型剪接的非Alu外显子下游插入左臂会使剪接从组成型转变为可变型。尽管两条臂高度相似，但左臂的特征是剪接信号较弱且外显子剪接调控（ESR）密度较低。改善这些潜在剪接信号的突变会激活外显子化，并使剪接从右臂转移到左臂。两个或更多推定剪接信号之间的协作赋予内含子左臂假外显子功能。因此，Alu元件的二聚体形式偶然为其提供了进化优势，使得灵长类转录组得以丰富，而不会损害其原始组成。
