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New discoveries on gene regulation in the evolution of the vertebrate brain

24 March 2011 Universidad de Barcelona

Alternative splicing of RNA transcripts is a process leading to differential gene expression and the production of different proteins, which is the key to cell differentiation and a foundation of many diseases. A group directed by Jordi García-Fernàndez and Gemma Marfany, from the Department of Genetics and the Institute of Biomedicine of the University of Barcelona (IBUB), has described the generation of a gene network regulated by the splicing factor NOVA1 during the development of the central nervous system in vertebrates.

 The study, published in the journal Proceedings of the National Academy of Sciences (PNAS), is signed by the first author Manuel Irimia, and was contributed to by Amanda Denuc, Demian Burguera, Ildiko Somorjai, Jose. M. Martín-Duran and Senda Jiménez-Delgado, from the Department of Genetics of the University of Barcelona, and by other experts from the University of Vienna (Austria) and Stanford University (United States).

 Over 90% of human genes, formed by introns and exons, generate multiple transcripts by a process known as alternative splicing, which facilitates the removal of introns (unexpressed fragments) and the combination of exons (expressed fragments) to form different proteins. Many hereditary genetic diseases are related to errors in the alternative splicing mechanism.

 The article in PNAS focuses on the NOVA1 (neuro-oncological ventral antigen 1) protein, a splicing factor involved in the differential splicing of RNA. NOVA1 is present in all animal groups, in particular vertebrates, and regulates the production of messenger RNA with specific tissue-related functions. In the case of the central nervous system, messenger RNA encode basic proteins related to ion channels, neurotransmitter receptors, molecules involved in synapse formation, etc.

 Previous studies had already confirmed the importance of NOVA1 in the architecture of the central nervous system. According to professor Jordi García-Fernàndez, “the study published in PNAS focuses principally on the generation of the NOVA1-regulated gene network and its development to full complexity in vertebrates, where NOVA1 specifically regulates tens or perhaps hundreds of genes in the central nervous system”.

 The study describes the stepwise assembly of the NOVA1-regulated splicing network during the evolution of metazoans. In the first step of this process, the NOVA1 protein acquired the ability to perform vertebrate-like splicing modulation, at the time of the emergence of chordates. In the second step, expression of NOVA1 became restricted to the central nervous system, just before the emergence of vertebrates. The third step saw NOVA1 acquire new exons and targets during vertebrate evolution.

 The study highlights that, despite containing a large number of similar genes, the human proteome is much larger and more complex than those of invertebrates. According to the conclusions presented, regulation of splicing factors and the creation of new exons are also key processes in the assembly of specific gene networks in complex systems – such as the human nervous system – via differential splicing.

Determining the alternative splicing mechanism of a specific gene in a tissue-specific manner is one of the most challenging areas in current research and crucial to understanding biological complexity. Despite the importance of alternative splicing, until now no study had been made of how these tissue-specific networks emerged and evolved to reach their current level of complexity in humans. According to Gemma Marfany, “rather than a new code, we are looking at a new form of increasing gene expression complexity: each gene, in addition to carrying a “code” in its regulatory region that controls when, where and how it is expressed, also has another level – alternative splicing – that identifies which proteins encoded by the gene are expressed in a particular tissue or at a given moment”.

 The study of alternative splicing in the human genome is one of the most challenging areas of genomic research. The difference between the human genome and those of other species stems less from the number of genes than from the large volume of differential transcripts generated (the transcriptome), which is now reflected in the wide variety of synthesized proteins (proteome), making this, as García-Fernández explains, “one of the most exciting research areas for geneticists”.

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