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Yet Another Blow to "Junk DNA": Paper Shows How Introns Are Key to the Splicing Code

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In the past, we've debated Darwinian advocates on the extent to which introns are functional, with those on the Darwin side steadfastly maintaining that they are largely useless genetic junk.

In that context, a news piece at Futurity, "'Junk' DNA hides assembly instructions," caught my attention. It explains that both exons (the parts of a gene that determine a protein's amino acid sequence) and introns (the intervening sections that are removed during protein assembly) affect the way genes are assembled. We've discussed this "splicing code" previously here on ENV, but basically it instructs cells how to mix and match pieces of RNA to create a myriad of different protein-coding mRNA transcripts from just a few genes. This helps explain how our cells can have so many diverse proteins but only, say, some 20,000 protein-coding gene regions in our DNA.

The lead author of the study, Yang Wang of the University of North Carolina, is quoted in the Futurity article stating that "the sequencing element in both exons and introns can regulate the splicing process" but "90 percent of the sequence is hidden in the gene's introns." Wang's research study, published in Nature Structural & Molecular Biology, "A complex network of factors with overlapping affinities represses splicing through intronic elements," explains why introns are extremely important in regulating this splicing code:

The specificity of splicing is mainly defined by splice-site and branchpoint sequences located near the 5′ and 3′ ends of introns. Beyond these core signals, multiple cis-acting splicing-regulatory elements (SREs) have essential roles in controlling splicing specificity. These SREs are conventionally classified as exonic splicing enhancers (ESEs) or silencers (ESSs) and intronic splicing enhancers (ISEs) or silencers (ISSs). SREs generally function by recruiting trans-acting splicing factors that interact favorably or unfavorably with the core splicing machinery such as the small nuclear ribonucleoprotein (snRNP) complexes U1 or U2. In mammals, the splicing of each gene is controlled by multiple SREs and corresponding splicing factors, whose combinatorial actions determine the final splicing outcome.

(Yang Wang et al., "A complex network of factors with overlapping affinities represses splicing through intronic elements," Nature Structural & Molecular Biology, Vol. 20:36-45 (2013) (internal citations omitted).)

The study sought to identify "intronic splicing regulatory elements" which regulate splicing in different ways, either by enhancing splicing or inhibiting it. The innovative study is elaborated in the Futurity article:
Their discovery was accomplished by inserting an intron into a green fluorescent protein (GFP) "reporter" gene. These introns of the reporter gene carried random DNA sequences. When the reporter is screened and shows green it means that portion of the intron is spliced.

"The default is dark, so any splicing enhancer or silencer can turn it green," Wang explains. "In this unbiased way we can recover hundreds of sequences of inhibited or enhanced splicing."

The study collaborators put together a library of cells that contain the GFP reporter with the random sequence inserted. Thus, when researchers looking at the intron try to determine what a particular snippet of genetic information does and its effect on gene function, they can refer to the splicing regulatory library of enhancers or silencers.

"So it turns out that the sequencing element in both exons and introns can regulate the splicing process," Wang says. "We call it the splicing code, which is the information that tells the cell to splice one way or the other. And now we can look at these variant DNA sequences in the intron to see if they really affect splicing, or change the coding pattern of the exon and, as a result, protein function."

Wang further observes that splicing "is a tightly regulated process, and a great number of human diseases are caused by the 'misregulation' of splicing in which the gene was not cut and pasted correctly." This implies that important protein products are produced by splicing, meaning that the splicing code plays an important functional role in cells.

Studies like this one add to the weight of evidence showing introns are vital -- in this case, for splicing of RNA to create important protein-coding transcripts. The "junk" in the genome turns out, once again, to be very much otherwise.