Alu-SINE exonization: En route to protein-coding function

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 occur-red 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.