New long-read sequencing reveals complete repertoire of isoforms of genes expressed in the brain


New research from the University of Exeter has shed light on the complexity of gene expression in the brain by characterizing the extent of isoform diversity in the human and murine cortex, including the identification of new isoforms of genes involved in diseases such as Alzheimer’s disease, autism and schizophrenia. Research suggests that the genes expressed in our brains can produce a lot more protein than previously thought.

We have about 20,000 genes encoded in our DNA sequence, but each gene can be expressed in many different versions – or isoforms – which are generated by a process called “alternative splicing”. This process can produce many isoforms of an expressed gene by sticking together different parts of the coding sequence in different combinations. Alternative splicing dramatically increases the complexity of genome coding and is important because these isoforms can have different functional properties that could play a role in health and disease.

Alternative splicing is known to be particularly important in the central nervous system, where it plays a role in brain development and function. In recent research published in Cell reports, and funded by the Medical Research Council and the Simons Foundation for Autism Research (SFARI), a team led by Professor Jonathan Mill used novel long-read sequencing approaches in Exeter to characterize complete transcripts and describe the complete repertoire of isoforms present in humans. and mouse brain. About half of the isoforms they detected had not been previously described, and the majority of these newer isoforms have the potential to encode proteins.

Isoforms have a wide range of functions, and it has long been known that alternative splicing plays an important role in regulating the function of genes in the brain, being implicated in many diseases of the brain. Today, we have characterized for the first time the different isoforms present in the human and murine brain, and also explored the differences occurring during brain development. Our study identifies thousands of new isoforms expressed in the brain and confirms the importance of alternative splicing in the cortex, dramatically increasing transcriptional diversity and representing an important mechanism underlying gene regulation in the brain. “

Szi Kay Leung, lead author

The team discovered major differences in isoform diversity for specific genes between human and murine brains, as well as large changes between the fetal and adult cortex, suggesting an important role for alternative splicing in neurodevelopment.

Lead author Professor Jonathan Mill, University of Exeter, said: “We are delighted to discover that genes associated with three brain diseases, Alzheimer’s disease, autism and schizophrenia, are characterized by many new isoforms not previously described. We are now exploring how these isoforms might play a role in the onset of the disease. “

Source:

Journal reference:

Leung, SK, et al. (2021) Complete transcript sequencing of the human and murine cerebral cortex identifies a wide variety of isoforms and alternative splicing. Cell reports. doi.org/10.1016/j.celrep.2021.110022.


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