For simplicity's sake, it's easy to think of the genome as a set of instructions that cells use to create the proteins that they need. There are around 20,000 protein-coding genes in the human genome, and the expression of these genes is carefully controlled to give cells their unique identities. But the reality is of course far more complex. There are non-coding portions of the genome and various other features of DNA like the epigenome that influence gene activity, as well as all the little sequence variations that arise in individuals. There are also different versions of genes themselves. When a gene sequence is transcribed from DNA into RNA, it can be processed in different ways, or alternatively spliced, to create variations of the same protein. Alternate isoforms have been implicated in some diseases.
New research has identified many gene isoforms are expressed only in the brain, and they may have different biological functions. In the central nervous system, alternative splicing is known to be common. This study used long-read sequencing to characterize full-length genes and their isoforms, outlining the various transcripts that are found in human and mouse brains at various periods in development. About half of these isoforms have not been identified before, and many have the potential to be translated into a protein. The work has been published in Cell Reports.
Thousands of new isoforms that are only expressed in the brain were identified in this study, which also confirmed "the importance of alternative splicing in the cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain," said lead study author Szi Kay Leung.
Human brains had a different level of isoform diversity than mouse brains, and in the cortex, the fetal brain was very different from the adult brain isoforms. Some disease-related isoforms were also found.
"We're excited to find that genes associated with three brain diseases, Alzheimer's disease, autism, and schizophrenia, are characterized by lots of new isoforms not previously described. We are now in the process of exploring how these isoforms might play a role in the onset of disease," said research leader Professor Jonathan Mill of the University of Exeter.
The research team noted that the isoform annotation data has been made publicly available here.