Alu-SINE Exonization: En Route to Protein-Coding Function

Abstract

The majority of more than one million primate-specific Alu elements map to nonfunctional parts of introns or intergenic sequences. Once integrated, they have the potential to become exapted as functional modules, e.g., as protein-coding domains via alternative splicing. This particular process is also termed exonization and increases protein versatility. Here we investigate 153 human chromosomal loci where Alu elements were conceivably exonized. In four selected examples, we generated, with the aid of representatives of all primate infraorders, phylogenetic reconstructions of the evolutionary steps presumably leading to exonization of Alu elements. We observed a variety of possible scenarios in which Alu elements led to novel mRNA splice forms and which, like most evolutionary processes, took different courses in different lineages. Our data show that, once acquired, some exonizations were lost again in some lineages. In general, Alu exonization occurred at various time points over the evolutionary history of primate lineages, and protein-coding potential was acquired either relatively soon after integration or millions of years thereafter. The course of these paths can probably be generalized to the exonization of other elements as well.

Biophysics of protein evolution and evolutionary protein biophysics

“…The term 'exaptation' (or 'spandrels' [138]; §2.4.1) has been coined for such latent traits that arise by chance and may or may not evolve to have a new function [379]. Apart from point mutations, mobile genetic elements are likely to play a crucial role in providing exaptations [380][381][382]. Each genome appears to constantly produce transcribed and translated 'proto-genes' that arise by chance, some of which may be exapted by evolution for a certain function [383].…”

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

“…Such co-opted or exapted modules can be derived from inter-or intragenic space and constitute novel protein-coding exons and regulatory regions such as promoters and enhancers (Brosius 2005b(Brosius , 2009Baertsch et al 2008;Rebollo et al 2012). 5 A prominent case is the exonization of parts of Alu elements, usually as alternatively spliced exons (Makalowski et al 1994;Nekrutenko and Li 2001;Sorek et al 2002;Lev-Maor et al 2003;Krull et al 2005;Shen et al 2011). Many such events are, over evolutionary time, not stable.…”

“…Should, over time, the novel splice variant happen to become beneficial, it will be under purifying selection and, by point mutations in and around splice signals, its ratio, in comparison to the canonical splice form, might change in its favor. In a phylogenetic study on primates, it has been shown that such exons derived from Alu elements are lost at a high rate in the trial and error mode, typical for the evolution of novelties (Krull et al 2005). A similar study involving all mammals and the older MIRs revealed that many of the events were already fixed and currently are under negative selection.…”

Modern origin of numerous alternatively spliced human introns from tandem arrays

“…The tandem genomic duplication of a portion of coding sequences with an AGGT cryptic splice site was initially proposed by Rogers (11) as a mechanism to produce the boundaries of a new intron. Although this model was rejected almost immediately based on the lack of similarity at the boundaries of introns that were examined, this mechanism was revived 10 years later to explain the origin of introns in several fish genes (12).A new intron can also arise when a known boundary is spliced to a novel junction created by point mutations, as is the case with the exonization of Alu elements (13,14). Recently, an intron in the SETMAR gene was shown to originate from the exonization of a mariner-like Hsmar1 transposon (15).…”

“…A new intron can also arise when a known boundary is spliced to a novel junction created by point mutations, as is the case with the exonization of Alu elements (13,14). Recently, an intron in the SETMAR gene was shown to originate from the exonization of a mariner-like Hsmar1 transposon (15).…”