'Junk' DNA vs The World

Proteins, proteins, proteins; Biologists are obsessed with them. Sure they are the reason us complex organisms can exist, but as a result of this infatuation with our polypeptide friends, we often overlook a rather important aspect of the human genome. Only 2% of our genome codes for proteins, and so until recently a large proportion of the other 98% was dismissed as 'junk' DNA. However, we are now realising that proteins may be the final end points required for life, but they could never be properly synthesised and organised without the junk genetic material. In fact, research into the genomic differences between more complex and simple organisms has concluded that the only genetic change that occurs as biological complexity increases is a greater percentage of DNA that does not code for proteins. Junk DNA can code for RNA, not the mRNA that is used for translation of proteins, but RNA that is functional in its own right! (more on this later) I personally feel betrayed by the A-Level Biology syllabus at this point... Anyway, the fact that Biologists were so focussed on the effect mutations had on protein coding DNA, meant that they were looking in the wrong neighbourhood of the human genome for the cause of inherited disorders like myotonic dystrophy. Within the myotonic dystrophy gene, a small base sequence (CTG) is repeated multiple times; 5-30 repeats in a healthy person. If the number of repeats exceeds 35, the sequence becomes unstable and can change in number erratically from one generation to the next, and as the the length increases generationally, the symptoms of the condition worsen, and develop earlier. At this point you're probably thinking; this is just a standard change in the base sequence of the gene, inhibiting the production of the correct protein. However, you would be wrong, as the amino acid sequence produced by this mutated myotonic dystrophy gene is unchanged, and the protein is still synthesised (did I just hear the jaws of the uninitiated drop?). Is this just an anomaly perhaps? Certainly not. Fragile X syndrome, the most common inherited learning disability, and Friedrich's ataxia, a muscle wasting disease, follow a similar mechanism. This was an unnerving revelation for researchers; there are mutations that can cause disease without changing the amino acid sequence of proteins. But in that case how do sufferers develop such debilitating symptoms? In Friedrich's ataxia, much like in myotonic dystrophy, the abnormally large section of repeats (GAA in the case of FA) is found between 2 sections of the protein coding genetic material(so in the junk DNA). Research has shown that when cells contained the expanded repeat, the production of mRNA encoded for by the gene was inhibited. The enlarged section of GAA repeats prevents accurate copying of the DNA, and thus there is no translation. In the case of Fragile X syndrome this means RNA around the cell is not properly regulated by Fragile X protein, causing cellular chaos and a life of disability for the sufferer. But that begs the question; why have the repeat sequences within the genes for myotonic dystrophy for example, been conserved over our genomic evolution? I mean, the repeats are located at the very end of the gene, so could easily be left out of any RNA produced. This means they must have a purpose in a healthy cell, within the mRNA of the gene. This is in fact the case, as the myotonic dystrophy mRNA is used to bind proteins in the cell (a weird role for mRNA), and the larger the repeat expansion, the more molecules are bound. The proteins are normally involved in the regulation of other mRNAs; controlling their lifespan and translation efficiency, and so without these regulatory polypeptides, the cell cannot function correctly. This discovery made sense to clinicians, as diseases in which a small change in gene expression creates such a huge impact on a patient, with fine tuning of severity between patients (based on length of repeats), are simply not observed. Therefore the role of this mutated junk DNA is more complex than we first thought, as it is not simply the number of abnormal repeats within the DNA that affects symptoms, but also the role of the expanded section of repeats on the mRNA synthesised from the mutated section of DNA in gene expression. From this paradigm it is clear that the fact that we have sequenced the human genome does not mean we understand all of its intricacies. Junk DNA has a powerful role, not just in inherited diseases, but in almost every aspect of our genome, and even our epigenome. That is why I'm so excited to continue this series, shedding light on the enigmatic sections of the genome previously condemned as insignificant junk.