The birth of new exons: mechanisms and evolutionary consequences

Abstract

A significant amount of literature was dedicated to hypotheses concerning the origin of ancient introns and exons, but accumulating evidence indicates that new exons are also constantly being added to evolving genomes. Several mechanisms contribute to the creation of novel exons in metazoan genomes, including whole gene and single exon duplications, but perhaps the most intriguing are events of exonization, where intronic sequences become exons de novo. Exonizations of intronic sequences, particularly those originating from repetitive elements, are now widely documented in many genomes including human, mouse, dog, and fish. Such de novo appearance of exons is very frequently associated with alternative splicing, with the new exon-containing variant typically being the rare one. This allows the new variant to be evolutionarily tested without compromising the original one, and provides an evolutionary strategy for generation of novel functions with minimum damage to the existing functional repertoire. This review discusses the molecular mechanisms leading to exonization, its extent in vertebrate genomes, and its evolutionary implications.

FIGURE 1.

Schematic model for exonization of an Alu element. (A) Alu is inserted into introns of primate genes by retrotransposition. (B) During the course of evolution, mutations within pseudo -splice sites in the intronic Alu activate these sites (black arrows). Mutations changing splicing regulatory elements are also possible (green arrow). (C) Following these mutations, part of the Alu sequence is recognized as a new exon (“exonized”), and spliced into the transcript. Typically, the Alu-containing transcript is the minor splice form, as in most cases the created splice sites are weak. Most exonizations involve the antisense orientation of the Alu sequence, presumably because of the preceding long poly-T that serves as a strong poly-pyrimidine tract necessary for the 3′SS recognition.

FIGURE 2.

The birth of an exon through RNA editing (Lev-Maor et al. 2007). Shown is a schematic illustration of the genomic region spanning exons 7–9 of the human NARF gene (not to scale). Exons are depicted as cylinders. The Alu element that is the source of the new exon is orange; an intronic, antisense orientation Alu sequence (light blue) is 25 bp upstream of the exonized Alu. Sense and antisense Alus fold to form a double-stranded RNA (dsRNA) secondary structure, thus allowing RNA editing to take place (lower panel). RNA editing changes an AA dinucleotide into a functional AG 3′ splice site and also changes a UAG stop codon into a UGG Trp codon. Thus, RNA editing leads to the creation of a new functional exon.