In the January issue of the journal Genome Research, two teams of scientists describe a widespread phenomenon in the human genome called transcription-induced chimerism (TIC), where two adjacent genes produce a single, fused RNA transcript. The work has implications for drug development, as well as for understanding mechanisms underlying gene evolution, transcription regulation, and genomic organization.
Dr. Roderic Guigo's group from the Centre de Regulacio Genomica (Barcelona, Spain), in collaboration with the group of Dr. Stylianos Antonarakis from the University of Geneva (Switzerland), and Dr. Rotem Sorek's team from Compugen (Tel Aviv, Israel) independently derived estimates that at least 2-5% of the genes in the human genome are involved in these events.
"In a certain way, this phenomenon challenges our very concept of a gene," points out Guigo. "The 'one gene, one protein' rule has been fundamental to molecular biology. However, as we deepen our understanding of the eukaryotic genome, a picture emerges that challenges this paradigm – not a picture in which the sequences in the genome have distinct functions, but rather one in which the sequences participate in multiple transcripts, encoding molecules with diverse functionality."
Sorek's team systematically identified over 200 cases of TIC involving 421 human genes. They found that genes involved in TIC events often reside closer together than other gene pairs in the genome. In addition, they discovered that the intergenic sequences of TICs were processed via the same standard eukaryotic splicing machinery that removes introns from RNA transcripts.
Following a similar whole-genome survey of splicing events, Guigo's laboratory focused on the ENCODE regions, a set of DNA sequences, representing 1% of the genome, that have been chosen by a large research consortium for more rigorous, in-depth analyses. When focusing on these regions, the researchers identified six TIC events (involving 3.6% of tandem gene pairs), only one of which was identified during the whole-genome survey. This indicates that future investigations of specific regions may reveal a greater prevalence of TIC events genome-wide.
Sorek's team unraveled an interesting gene fusion event involving genes called PIP5K1A and PSD4, which reside side by side on human chromosome 1. These genes produce a fusion product that, during the course of evolution, inserted into a different location in the human genome (chromosome 10), becoming a new gene that is actively transcribed in a variety of tissues.
"Our findings might have applications in drug development," says Sorek. "Recombinant engineered fused proteins are currently being developed as therapeutic proteins by several companies and institutes. The problem is that these proteins often elicit an immune response and therefore, are toxic and cannot be used as efficient drugs. The understanding that some gene pairs are naturally produced as fused proteins might lead, in the future, to the development of non-toxic engineered fused proteins that could be used as drugs."