Novel mechanism splices genes in the human 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.

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