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.

Genome-wide discovery of human splicing branchpoints

“…Focusing on specific types of alternative splicing events, we find a global shift toward weaker B-box elements for skipped exons (P < 0.001), but not within retained introns (one-way ANOVAKruskal-Wallis test with Dunn's post-test). B-boxes associated with alternatively spliced exons are also more conserved (1.90-fold, P = 3.1 3 10 À5 , unpaired t-test) than counterparts at constitutive exons, a trend similarly observed for other splicing elements (Sorek 2007).…”

Widespread establishment and regulatory impact of Alu exons in human genes

“…The origin and evolution of new exons have attracted considerable interest in recent years (6). Although lineage-specific exons are common in mammalian genomes, identifying those exons that have genuine biological functions is a major challenge.…”

“…The consensus sequence of Alu harbors sites that resemble the 5′ and 3′ splice site signals (5,6). After the insertion of an Alu element into the intronic region of an existing gene, subsequent mutations could activate these splice sites or introduce additional splicing regulatory signals, leading to the creation of a new exon (6).…”

“…The consensus sequence of Alu harbors sites that resemble the 5′ and 3′ splice site signals (5,6). After the insertion of an Alu element into the intronic region of an existing gene, subsequent mutations could activate these splice sites or introduce additional splicing regulatory signals, leading to the creation of a new exon (6). Although the vast majority of Alu exons are rarely incorporated into transcripts (7), the analyses of expressed sequence tags (ESTs) and exon array data recently have revealed a small number of Alu exons with high splicing activities or tissue-specific splicing profiles (8,9).…”

When new exons are born

“…Intriguingly, it has been shown that some Alus can be 'exonized', that is, turned into new exons. Such exonizations occur when random mutations activate 'hidden' splice sites within the Alu sequences, so that the splicing machinery recognizes part of the Alu element as a bone fide exon (Sorek, 2007).…”