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Move Over, Proteins – Science Says it’s an RNA World Now. But is it?

Hello, folks. Back in September, a seminal group of works were published in Nature and Science which revealed that contrary to our once-protein-centric view of genetics, the majority of gene products are in fact RNA, not protein [1]. While our genome contains close to 32,000 genes and pseudo-genes across 3 billion bases, approximately 76% of the genome is actually transcribed. This revelation has been staggering to many within the scientific communities, reminding us once again that the Central Dogma of Molecular Biology is really more dogma than biology and not quite as central as we once believed.

While this paradigm shift is a welcome relief to those of us agnostics whose faith has long been shaken in the Almighty Protein, I for one am not eager to reassign my wandering faith to a different placeholder deity either. RNA is certainly long due for its time in the limelight, but such a shift in loyalties ignores the fact that the cell is a gestalt and the complexity with which it has been imbued over the last 3.7 billion years is an inseparable biochemical collective that is defined by no single constituent. Origins of Life research may suggest that various nucleic acids, proteins, or even geochemicals were the earliest building blocks of proto-life, but these were merely scaffolds to the evolution of cells as we know them today. Life is no longer represented by the formation of amino acids in a test tube; it’s a culmination of nucleic acids, proteins, carbohydrates, lipids, metals, and other organic and inorganic compounds. In short, it’s a system whose parts are no longer separable.

Nevertheless, you have to admit that 76% is a profoundly impressive– and dare I say cool?– number. But various scientific communities have been aware of the importance of RNA transcripts in cellular function beyond that of their intermediate roles for some time now. Just look at the numerous microRNA and lincRNA studies which have littered the literature over the last decade. And clinically-oriented scientists are beginning to catch up. For instance, scientists studying autism have recently had an AH-HA moment, proclaiming that mutations in patients occur not just in protein-coding sequences but in non-coding, e.g., untranslated sequences, as well [2]. In fact, if you take a little stroll to AutismKB to select a few risk-genes at random, gather a listing of specific mutations, and then wander over to Ensembl to get your base sequence, you’ll find that a large percentage of mutations occur upstream or intronically, not generally within protein-coding sequences.

Let’s continue using autism for an example to belabor a point however. For years, scientists have slowly been building a picture of the heterogeneous condition which is simultaneously and extraordinarily detailed, but a picture so complex that drawing relevance from the larger body of literature is damn near impossible. For this, I would turn to Graham Cairns-Smith, noted Origins of Life researcher and novel-idea-thinker:

Faced with a really difficult-looking problem should one follow the advice of Descartes or of Holmes? Should one proceed step by step from what is easily understood, as Descartes advised, ‘starting with what was simplest and easiest to know, and rising little by little to the knowledge of the most complex’? It sounds like good advice and on the whole modern science takes it. But the methodical step-by-step strategy does not always work. First steps can be particularly tricky and you have to know in which direction to go. There are times when you need the advice not of Descartes, but of Sherlock Holmes (p. ix).

From there Cairns-Smith expounds on Holmes’ seemingly incomprehensible talent to pick out the oddest piece of evidence, that singularly striking feature, and fashion his case outward.

They can point the way. They can tell you what sort of a problem it is that you are dealing with. If you can see how the murder could have been done at all with the door and the windows securely fastened…, or if you can understand why on earth the thief should have rung the bell that gave away his presence in the room…, why then, you may even have cracked the whole thing (p. ix).

Contrary to a trend which may now shift geneticists and molecular biologists away from proteins and towards RNA products, I must remind the communities that it isn’t always about variations in product formation. In fact, there are three basic outcomes of a given mutation, one of which is often overlooked:1) The effects are neutral and nothing of significance occurs;2) A sequence change occurs within some sort of protein or RNA coding sequence which potentially changes the activity of the product, for good or for bad;3) A sequence change occurs within intergenic, enhancer, promoter, or intronic regions, which subsequently alters the overall conformation of the local DNA and ultimately changes how the usual slew of biomolecules, metals, and other organic and inorganic molecules bind to the genome and affect transcription of downstream products.

#2 is the outcome which has received considerable attention in research. And because outcome #3 is the most daunting to predict, requiring both generalized and nuanced knowledge of how the genome interacts with itself and other biomolecules, it is the outcome which has garnered the least amount of attention. When scientists study mutations associated with conditions like autism, most of the subsequent literature centers around changes in gene product and how those products may somehow be involved in the etiology of a condition. It’s a worthy avenue to follow, but not the only one when considering possible outcomes following genetic mutation.

For me, Holmes’ ringing bell is the fact that even though single nucleotide polymorphisms (SNP) and copy number variants (CNV) in autism occur in higher frequency, they occur over such a wide variety of genes that it is almost impossible to fashion a smoking gun from such diverse products [3; 4]. Unless mutations within autism are not necessarily a causal factor in all cases but are instead yet another symptom of the conditions.

How could that be? you ask. Quite simply: target the epigenome and you can promote specific types of mutations. The epigenome is an amazing thing that can not only modulate product expression but can also alter the genome’s flexibility and overall stability. It is likely how an incredible array of mosaicism occurs across cell types within your body and probably also a key player in cancer development  [5, for example; 6]. Therefore, what is common to autism may not be the genome but the epigenome, and autism’s relationship to teratogens such as valproic acid and thalidomide may help bear this out.

This is not to say that altered gene products don’t play roles in autism; I’d expect they often do. But they are not the lowest common denominator in the conditions; instead, the simple fact that these diverse mutations exist at all is far more intriguing. And it’s also true that not all autistic people house noteworthy mutations, and so the factors which converge on common etiology do not lie at the level of the gene.

Nevertheless, chromosomes are beautifully flexible, mutable, 3-dimensionally interactive macromolecules. They don’t lie in wait like some timid lover but aggressively seek their molecular partners, offering welcoming curves to a desired protein, RNA, or metal, and then in an instant change direction and rebuff their partner’s advances. In light of this new RNA revelation, I will be sad to see protein-turncoats move from one camp to another, perpetually focused on The Gene Product and always failing to appreciate the dynamism of the genome itself and the big picture of the indivisible biochemical system we call a Cell. Because of this, the complexity of knowledge surrounding conditions like autism may remain indefinitely overwhelming.

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