A new genetic switch uncovered in the long genes expressed in our brain
14 May 2015
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
Further information:
- Sibley et al. Recursive splicing in long vertebrate genes Nature (2015). Available online 13th May 2015. doi:10.1038/nature14466
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Dr Ule's academic profile on IRIS
- Dr Sibley's academic profile on IRIS
- Dr Plagnol's academic profile on IRIS