A new genetic switch uncovered in the long genes expressed in our brain

Researchers at UCL (University College London) have discovered a new mechanism for 'splicing-based' gene regulation, with possible implications for brain-related disorders.

Most of our genes contain introns and exons. After the genes are transcribed into RNA, the introns are removed by 'splicing' and exons are joined together to form a messenger RNA (mRNA), which contains the instructions for making a protein. In this study the scientists found that cells sometimes select a piece of a gene as an exon, but later discard it, in a process called recursive splicing.

They observed this process happening in some of the longest genes that are expressed in the brain, which are often implicated in autism or other neurodevelopmental disorders. The process is coordinated by so-called 'recursive sites', which are highly conserved in mammals, and in one case even from fish to humans.

Likening the process to making a film, Professor Jernej Ule, who led the research with Dr Vincent Plagnol (both of UCL) said: "Our genes are like a raw footage for film. Just like the individual shots are combined into the motion picture, the exons are selected and combined into the mRNA.

"We show that most of the longest genes in our genome are primarily expressed in the brain. The brain appears to be a very demanding director, which needs an extraordinary amount of raw footage and special mechanisms like recursive splicing to produce the motion picture."

Long introns in genes contain hundreds of so-called 'cryptic sequences', which could be used to direct the splicing process. This means that the cellular machinery faces great challenges in distinguishing true exons from those that that appear very similar to exons, but are not supposed to be used.

The scientists used a technique called high throughput DNA sequencing to identify many previously unobserved splicing events within long introns. They then examined the mechanisms that distinguish genuine splice sites from cryptic splice sites.

Surprisingly, the study found that some of the cryptic splice sites are actually highly used and authentic splice sites, even though they have not been discovered before. This led to discovery of recursive sites that are present deep within extremely long introns. The scientists found that a recursive site is initially defined as an exon, but is later removed, allowing it to remain invisible.

"However, if the recursive site is preceded by other cryptic splicing events, then the exon is not removed - creating a 'binary switch' or checkpoint that can distinguish correct splicing events from the newly emerging cryptic events, which could be potentially damaging," explained Dr Christopher Sibley, also of UCL.

Professor Ule said: "Even though cryptic splicing is often damaging, it allows new exons to emerge, which plays an important role in the rapid evolution of the brain. Long introns increase the frequency of cryptic splicing.

"Thus, long introns on one hand enable evolutionary tinkering, whereas recursive splicing ensures that this tinkering does not disturb the primary mRNA that needs to be made from the gene."

"This study is an important step towards understanding the role of non-coding elements in genes," added Dr Plagnol. "Accordingly, attention should be paid to these sites in future studies of disease-causing mutations, especially for brain-related disorders, as this is the organ where these long genes are predominantly expressed."

The paper, Recursive splicing in long vertebrate genes, is published in Nature.

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