The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of new gene formation. It is observed across vertebrates, invertebrates, and in some plants such as potatoes and sunflowers. During exon recombination, exons from the same or different genes recombine and produce new exon-intron combinations, which might evolve into new genes.

Exon shuffling follows “splice frame rules.” Each exon has three reading frames. The incoming exons can recombine and join at any one of the three reading frames and cause frameshift mutations. Therefore, not all recombination events are useful; some can even result in a premature stop codon and immature protein.

Exon shuffling in the human genome

Along with gene duplication and divergence, the exon shuffling is attributed to the evolution of several human-specific genes. For example, around 25 million years ago, a gene called MCH (Melanin-concentrating hormone) underwent exon recombination by retrotransposition in the early primates. It created de novo intron-exon boundaries, which later evolved into the Hominidae specific conserved gene PMCHL1 - although this is a pseudogene, the antisense RNA is expressed in the human brain. Since the original MCH gene encoded a neuropeptide involved in balancing energy requirements and body weight in rodents, the PMCHL-1 is expected to have similar functions.

Illegitimate recombination (IR) is one of the most commonly observed mechanisms of exon recombination or exon shuffling. IR leads to duplication of exons; this has been observed in several human diseases such as Duchenne and Becker muscular dystrophy, familial hypercholesterolemia, Lesch-Nyhan syndrome, hemophilia, and lipoprotein lipase deficiency.