17 September 2020
Novel mechanism splices genes in the human brain
Published online 20 May 2015
A newly discovered mechanism for gene splicing in the brain could explain some mysteries of the brain.
A new study shows that some of the longest genes active in our brain are processed by recursive splicing, a mechanism previously only seen in Drosophila. Understanding how this process works may shed light on the evolution of these genes and disorders in which they malfunction1.
Researchers from several institutes, including University College London in the UK and the King Faisal Specialist Hospital and Research Centre in Saudi Arabia, used high-throughput RNA sequencing to investigate how long genes were spliced in four post-mortem human brains.
Long introns in these genes are removed in two steps, or recursively spliced. The researchers found that the process requires a cryptic exon which is hidden within the introns and normally removed without a trace during recursive splicing.
However, the cryptic exon is retained if it is preceded by another cryptic exon. Recursive splicing thus creates a binary switch between isoforms with and without the cryptic exon. Since the cryptic exon includes a premature stop signal, isoforms which include it are usually inactivated and destroyed, although they may be retained.
“We propose that the binary switch acts as a filter for new isoforms of long genes, allowing the evolution of the brain to proceed in a more gradual and controlled manner,” says Jernej Ule, the UCL researcher who led the study. Recursive splicing may also have clinical significance, since mis-expression of these long genes has been linked to autism and other neurological disorders.
- Sibley, C. R. et al. Recursive splicing in long vertebrate genes. Nature http://www.dx.doi.org/10.1038/nature14466 (2015).