[2] Exon shuffling was first introduced in 1978 when Walter Gilbert discovered that the existence of introns could play a major role in the evolution of proteins.
[citation needed] In order for exon shuffling to start to play a major role in protein evolution the appearance of spliceosomal introns had to take place.
[citation needed] Moreover, to define more precisely the time when exon shuffling became significant in eukaryotes, the evolutionary distribution of modular proteins that evolved through this mechanism were examined in different organisms such as Escherichia coli, Saccharomyces cerevisiae, and Arabidopsis thaliana.
These studies suggested that there was an inverse relationship between the genome compactness and the proportion of intronic and repetitive sequences, and that exon shuffling became significant after metazoan radiation.
[4] Evolution of eukaryotes is mediated by sexual recombination of parental genomes and since introns are longer than exons most of the crossovers occur in noncoding regions.
In these introns there are large numbers of transposable elements and repeated sequences which promote recombination of nonhomologous genes.
In addition it has also been shown that mosaic proteins are composed of mobile domains which have spread to different genes during evolution and which are capable of folding themselves.
Additional information has led to the belief that trans-mobilization of the DNA sequence is another mechanism of L1 to shuffle exons, but more research on the subject must be done.
Helitron transposons were first discovered during studies of repetitive DNA segments of rice, worm and the thale crest genomes.
[citation needed] Helitron encoded proteins are composed of a rolling-circle (RC) replication initiator (Rep) and a DNA helicase (Hel) domain.
It is composed of the read-through Helitron element and its downstream genomic regions, flanked by a random DNA site, serving as a "de novo" RC terminator.
Lastly in the FDNA model portions of genes or non-coding regions can accidentally serve as templates during repair of ds DNA breaks occurring in helitrons.
[citation needed] Long-terminal repeat (LTR) retrotransposons are part of another mechanism through which exon shuffling takes place.
The second ORF named pol is a polyprotein composed of an aspartic protease (AP)which cleaves the polyprotein, an Rnase H (RH) which splits the DNR-RNA hybrid, a reverse transcriptase (RT) which produces a cDNA copy of the transposons RNA and a DDE integrase which inserts cDNA into the host's genome.
Retrotransponsons synthesize a cDNA copy based on the RNA strand using a reverse transcriptase related to retroviral RT.
[citation needed] DNA transposon with Terminal inverted repeats (TIRs) can also contribute to gene shuffling.
[11] This process appears to be mediated by acquisition of genic DNA residing between neighbouring Pack-TYPE transposons and its subsequent mobilization.