Splicing in Human Genes

            Intron splicing discussed in the previous article was on a whole new level for me. Chasing some links under “similar articles” I found this journal, which focuses on the splicing of introns in regards to human genes. Since this article deals with human genes it hits closer to home so let’s get started.

           

            Splicing of many human geens involves sites embedded within introns by Kelly et al., want to challenge the old ways of looking at splicing and open the door for a broader sense of what splicing is. The conventional method of splicing and introns, regarded as “junk”, that they want to question is the that the 3’ end of one exon directly connects to the 5’ prime end of another exon with the introns completely removed from the equation. They also explore how genes yield products generated by intermediate intron splicing and how inhibiting the intermediate splicing prevents efficient exon-exon splicing.

            The diagram below shows the differences between the conventional model versus the recursive model that the authors experiment with.

             As mentioned before, the conventional model has 3’ end of one exon (donor) meet with the 5’ end of another exon (acceptor) joined together. The recursive model has the 3’ end join to sites within the intron, RS1 and RS2, before combining with the 5’ end. What the diagram is trying to show is how introns removal assist in the completion spliced sequence. Having the 3’ end of the exon connect with RS1 and RS2 it increases the splicing efficiency by bringing the 3’ end to the 5’ end in sequential steps rather than one big jump. A big jump could cause errors or difficulties due to the intron’s length, which is very long in human genes.

            Continued experimentation revealed that mutations of the RS sites negatively affect the amount of mature exon-exon products. The diagrams below demonstrate the effects of mutations.

           

            These diagrams show a series of events of how the RS sites can be mutated and no longer functioning. The comparison was done between the mutants and wild types. The exons themselves are maintained but the completed splice and mature mRNA decrease due to the lack of RS sites present.

            At the end of their experimentation the authors concluded that the introns and their RS sites directly correlate with exn-exon splicing and the production of mature mRNA. They also state that the RS sites can act as regulatory sites to limit the overproduction of certain proteins. The exact mechanisms of the RS sites and their influence on splicing remains unclear and further studies are needed.

            The experimentation done by the authors on human genes made this journal more interesting by demonstrating that nothing in the DNA or the body is junk. The cost-benefit analysis on introns thus far reveals that introns are an important factor in regulation and gene splicing. Despite initial concerns of the amount of DNA sequence that they take up. Learning more and more about introns is flipping some of my fundamental ideas of DNA and gene expression upside down. The introns, promoters, poly-A tails, and so on show me how much of the DNA is used to actually get those genes through the process of transcription and translation.   

Sources:

Steven, K., Georgomanolis, T., Zirkel, A., Diermeier, S., O’reilly, D., Murphy, S., Langst, G., Cook, P.R., & Papantonis, A. (2015). Splicing of many human genes involves sites embedded with introns. Nucleic Acids Research. 43: 4721-4732.