A new mechanism for splicing-based gene regulation has been discovered in vertebrates by a team of researchers at UCL Institute of Neurology and UCL Genetics Institute, showing that sometimes cells select a piece of a gene as an exon, but then later discard this piece in the process called ‘recursive splicing’.

This process was observed in some of the longest genes that are expressed in the brain, which is of clinical significance, since these genes are often implicated in autism or other neurodevelopmental disorders.

The study published in Nature reports newly discovered recursive sites that are highly conserved in mammals, and in one case even from fish to human. The genes containing recursive splice sites are among the longest genes in vertebrate genomes, because they contain extremely long introns.

Our genes are like a raw footage for film, where individual shots need to be selected and combined into the full motion picture. In the genes, the selected shots are called ‘exons’, whereas the parts to be discarded are called ‘introns’.

The exons of a gene are combined together during a process called splicing in order to create the messenger RNA (mRNA). These mRNA molecules contain the instructions for producing the proteins that keep our cells functioning. Moreover, in our genes, different shots can be selected and combined into different variants of the motion picture via alternative splicing.

This mechanism increases the complexity of mRNAs and proteins that are made from the limited number of ~20,000 genes present in human genome. This is particularly important for the cells in the brain, allowing them to perform complex brain functions that enable us to think and learn.

Long introns contain literally hundreds of cryptic sequences that could be used to direct the splicing process, and thus 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 present study used high throughput DNA sequencing to identify many previously un-observed splicing events within long introns, and then examined the mechanisms that distinguish bona fide splice sites from cryptic splice sites. The study finds that recursive sites are initially defined by an exon, which is later removed, and therefore it remains ‘invisible’.

The study was supported by the European Research Council, the Medical Research Council, Cancer Research UK and the National Institute for Health Research

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