2.7
Exon Recombination
The evolution of new genes is critical for speciation. Exon recombination, also known as exon shuffling or domain shuffling, is an important means of…
Eukaryotic genes consist of alternating blocks of protein-coding sequences called exons and noncoding sequences called introns.
Exon recombination is a process where the exons from the same or different genes recombine to produce novel combinations of exon-intron sequences, which might evolve into new genes.
The exon recombination can be mediated by non-homologous recombination or retro-transposition.
During non-homologous or illegitimate recombination, DNA strands with no sequence similarity can recombine and produce a novel gene structure.
Chronic granulomatous disease - a genetic disorder of the immune system is a good example. Many patients with this disease have a rare mutation in the phox gene coding for the enzyme NADPH oxidase.
The wild type NADPH oxidase produces reactive oxygen species such as superoxide upon infection and aids in phagocyte-mediated killing of the infectious agents.
In rare cases, the non-homologous sequences between exons 8 and 11 of the phox gene recombine, causing duplication of exons 9 and 10. This leads to the reduced activity of the enzyme NADPH oxidase. The impaired enzyme fails to generate enough reactive oxygen species to clear the bacterial infection resulting in granuloma or aggregation of macrophages and associated immune cells.
Exon recombination due to retrotransposition can best explain the evolution of the Jingwei gene in African Drosophila.
Around 2.5 million years ago, a portion of the Adh mRNA reverse-transcribed into DNA and recombined with exons of the Ynd gene to give rise to a new gene called Jingwei.
The Ynd gene is responsible for the development of testes in drosophila and the Adh gene encodes alcohol dehydrogenase. The new gene Jingwei encodes a protein with two domains - one derived from Ynd and the other from Adh.
Hence, the protein Jingwei is expressed in the drosophila testis and is responsible for hormone and pheromone biosynthesis.
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Q1: What is exon recombination and how does it contribute to gene evolution?
Exon recombination, also called exon shuffling, is a process where exons from the same or different genes recombine to produce novel combinations of exon-intron sequences that may evolve into new genes. This mechanism is critical for speciation and has been observed across vertebrates, invertebrates, and some plants. It works alongside gene duplication and divergence to generate genetic diversity and new protein functions.
Q2: What are the two main mechanisms that mediate exon recombination?
Exon recombination is mediated by non-homologous recombination and retrotransposition. Non-homologous recombination occurs when DNA strands with no sequence similarity recombine to produce novel gene structures. Retrotransposition involves reverse transcription of mRNA into DNA, which then recombines with exons of other genes to create new genetic combinations.
Q3: How does illegitimate recombination lead to genetic disease?
Illegitimate recombination can cause exon duplication, leading to altered gene function and disease. In chronic granulomatous disease, non-homologous sequences between exons 8 and 11 of the phox gene recombine, duplicating exons 9 and 10. This reduces NADPH oxidase activity, impairing the enzyme's ability to generate reactive oxygen species needed to clear bacterial infections, resulting in granuloma formation.
Q4: What are splice frame rules and why do they matter in exon shuffling?
Splice frame rules govern how exons recombine during exon shuffling. Each exon has three reading frames, and incoming exons can recombine at any of these frames, potentially causing frameshift mutations. Not all recombination events are useful; some create premature stop codons and produce immature proteins, limiting the success of exon shuffling events.
Q5: How did the Jingwei gene evolve through exon recombination in Drosophila?
Approximately 2.5 million years ago, a portion of Adh mRNA reverse-transcribed into DNA and recombined with exons of the Ynd gene, creating the new Jingwei gene through retrotransposition. The resulting protein contains two domains: one from Ynd and one from Adh. Jingwei is expressed in the Drosophila testis and functions in hormone and pheromone biosynthesis.
Q6: What is the PMCHL1 gene and how did it arise from exon recombination?
PMCHL1 is a human pseudogene that arose around 25 million years ago when the MCH gene underwent exon recombination by retrotransposition in early primates. This event created new intron-exon boundaries that evolved into the Hominidae-specific PMCHL1. Although a pseudogene, its antisense RNA is expressed in the human brain and likely retains functions related to energy balance.
Q7: Which human diseases result from illegitimate recombination causing exon duplication?
Illegitimate recombination is a common mechanism of exon duplication in several human genetic disorders. These include Duchenne and Becker muscular dystrophy, familial hypercholesterolemia, Lesch-Nyhan syndrome, hemophilia, and lipoprotein lipase deficiency. Each disease results from exon duplication that disrupts normal gene function and protein production.