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 . 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 . 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.
I enjoyed reading your post and although I don’t claim to be an expert on Molecular Biology. I do have a question which might be more of a generalization. Would or could comment as to whether “junk DNA” can play a role in “development” of autism? Or worded differently, does a drug like valproic acid or thalidomide affect the DNA in a manner that these substances will replace one of the bases in DNA–thus causing the unwanted problems?
Hi, jaksichja. That’s a very good question. In fact, I have a book chapter currently in press dealing with precisely those issues. For VPA, for instance, there is a moderate amount of evidence to suggest that it’s not only a teratogen which is now well established but also a potential mutagen, though further studies are necessary. While studies have not investigated the types of mutations which could arise following exposure, studies have reported increased occurrence of double-strand breaks (DSB), which is where the chromosome is broken and then repaired, leaving tell-tale signs of the earlier breakage event. Just from my own experience, I would expect both copy number variations and closely-related SNPs to follow such breakages. The chapter I wrote focuses on VPA’s inhibition of histone deacetylase (HDAC) as a potential genomic destabilizer. If you’d like a copy of the upcoming chapter, please email me at “el will 08 @ louisville.edu” (minus the spaces) and I’d be happy to send it to you and answer any further questions.
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Over at Pharyngula, PZ Myers apparently decided that we’d corresponded quite enough for his likes. So he “moderated” a comment of mine thanking you for yours-moderated it into oblivion. I hadn’t saved a copy, but I send you this, with references to articles Myers, in his tiny imagination, didn’t deem interesting enough to be posted:
“The Origin of Indioviduals” (2009, World Scientific; New Jersey)
“A Darwinian theory for the origin of cellular differentiation”
Volume 110, Issue 1, Pages 1-150 (September 2012)
Progress in Biophysics and Molecular Biology
Special Issue: “Chance at the heart of the cell”
Edited by Jean-Jacques Kupiec, Olivier Gandrillon, Delphine Kolesnik and Guillaume Beslon
also of interest:
“Clonal clues reveal cancer chaos”
Please know I saw your response and here are my thanks for it. As to why Meyers did that? All I can say is that apparently he didn’t like/approve the thrust of the articles–they are indeed a challenge to standard theory. However, my impression is that these articles and more of the sort are things that you are going to find simply fascinating. With them as a start and your knowledge of locating current research, I doubt that you’ll need further recommendations from me because each one presents related papers, other researchers doing work that is similarly interesting.
In your rather open-minded view of these issues, you’re very different from what I’ve had to become used to in all other science blogs I frequent. And, since your area of research is very near what most interests me, I expect I’ll continue to follow your postings here and maybe occasionally add a word. Please excuse my piggy-backing on this thread–though it’s very interesting in its own right.
The work of Kupiec has profound implications for every aspect of cell life, and, not least, the matter of so-called “junk DNA,” which jaksichja mentions, above. Briefly, as I understand Kupiec and Pierre Sonigo, (in esp. “Ni Dieu, ni gène” (2000; Seuil, Paris) there really is no such thing as junk DNA–perhaps it ought to be considered is our biological “growing-room” where nature’s and nuture’s happenstance events will mark and score the material changes of living experiences and a random-generating factor, as strands wind and wind into multiple and complex 3-D forms.(and unwind in reverse ) thereby “placing” molecules in greater or lesser proximity to the other molecules whose positions will offer interactive potentials for reaction, sythesis, etc.
much good luck in your work and research –as the world is ruled by random events. ;^)
>>there really is no such thing as junk DNA–perhaps it ought to be considered is our biological “growing-room” where nature’s and nuture’s happenstance events will mark and score the material changes of living experiences and a random-generating factor<<
I just have to say as a side note, as a now-scientist-but-once-creative-writing-major, your turn-of-phrase is lovely. 🙂
Thank you, by the way, for the compliments. I hope to keep an open mind. (If I ever start sounding unopen, please feel free to politely cyber-slap me!). Thankfully, imperfections in theory tend to niggle at me until I find something more fitting to my mind, so I'm in perpetual revision. I'm glad the blog is something new to you. I have to admit, I'm not much traveled in the blogosphere and this whole "internet networking thing" is also novel. But so far it's been fun and I look forward to having a good number of back-and-forths with you and other respondents in future. 🙂
proximity1, well that silly bugger! Wonder why Meyers did that; I didn’t think we were talking too much. Ah well. Thank you very much for the materials! I’ll have to see about getting the book through interlibrary loan. And the articles both look excellent. Do please feel free to recommend other works to me in future. 🙂