The SRP, Alu Elements, and Nudging

I’ve combined the essays about the signal recognition partcle, Alu elements, cytosine deamination, all connected by front-loading. All 11, 465 words of it.

Alu Behind Learning and Memory?

I’ve been wanting to comment on this article by Mattick and Mehler, but have just been too busy. Luckily, I just ran across a web article that borrows heavily from M&M’s article. I would encourage you to read the whole thing (if you can’t get your hands on M&M’s article, that is). Here are some excerpts:

More Alu on the Brain

RNA editing, DNA recoding and the evolution of human cognition.

Mattick JS, Mehler MF.

Trends Neurosci. 2008 May;31(5):227-33.

RNA editing appears to be the major mechanism by which environmental signals overwrite encoded genetic information to modify gene function and regulation, particularly in the brain. We suggest that the predominance of Alu elements in the human genome is the result of their evolutionary co-adaptation as a modular substrate for RNA editing, driven by selection for higher-order cognitive function. We show that RNA editing alters transcripts from loci encoding proteins involved in neural cell identity, maturation and function, as well as in DNA repair, implying a role for RNA editing not only in neural transmission and network plasticity but also in brain development, and suggesting that communication of productive changes back to the genome might constitute the molecular basis of long-term memory and higher-order cognition.

Alu Mania

I’ve been talking about Alu elements for weeks now, so I was going to try to change the topic.  But alas, I can’t stop myself.  Here is some more Alu Fun for those similarly intrigued by the manner in which these nifty reformatting devices can facilitate evolution.

First, here is a decent video that outlines the basics of Alu retrotansposition.

Second, remember how it has become clear that the genome has a three-dimensional architecture?

Nudging the nudge

We have seen that the Alu element is poised to generate binding sites for multiple transcription factors involved in development.  Even more interesting is the manner in which the process of cytosine deamination can easily create several of these transcription factor binding sites.  It’s as if we have two nudges, working together, to facilitate the evolution of primates.

Yet there is more to the story.  Recall that the cytosine deamination events occur at CpG sites.This is simply where a cytosine (C) is followed by a guanine (G).  Why is this?

It just doesn’t stop!

The title of yet another paper speaks for itself: Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes (Paz Polak and Eytan Domany. BMC Genomics. 2006; 7: 133).

Let’s look at the abstract.

This research suggests that evolution used transposable elements to insert modules of transcription factor binding motifs into promoters and, by means of their presence, assemble higher level regulatory networks. In order to explore this question we focused on Alu elements, which are good potential candidates to be part of the building blocks of regulatory networks for two reasons. First, Alu elements are abundant in the upstream region of the TSS of genes, and second, Alu elements contain dozens of putative BSs for TFs. Some of these BSs were found before and their association with Alu was also reported, whereas in some cases although the BSs were found, the fact that they reside on Alu went unnoticed. Finally, we list here also BSs on Alu that were not identified previously. Our findings imply that the biological pathway on which Alu-mediated regulation appears to have the most significant impact is the development process. Many of the TFs that have binding motifs on Alu are associated with development; moreover, some of these BSs were previously demonstrated to be functional in vivo and essential to regulation of some target genes.

TF stands for transcription factors, proteins that bind to specific DNA sequence to activate the process of gene expression.  TSS stands for transcription start site, the precise point at which the copying of the DNA into an RNA format begins.  BS stands for binding site, the region of the DNA that binds with the transcription factors.

You too, p53?

p53 has been called the “Guardian of the genome” and is commonly known as a tumor-suppressor gene – a gene that suppresses the formation of cancer.  Normally, the cell expresses low levels of the p53 protein, but if the genome is damaged, p53 levels rise and in turn activate several programs that will arrest the cell cycle and attempt to repair the DNA damage.  If the genome cannot be repaired, p53 will then activate programmed cell death and the cell will die rather than pass on the damage to future generations.

You too, Pax6?

From Novel PAX6 Binding Sites in the Human Genome and the Role of Repetitive Elements in the Evolution of Gene Regulation, by Yi-Hong Zhou, Jessica B. Zheng, Xun Gu, Grady F. Saunders, and W.-K. Alfred Yung.

Why RAREs are not so rare

From this site, we learn

Retinoic acid (RA) may act as a regulator of differentiation at various stages of vertebrate embryogenesis. In particular, the results of exogeneous RA treatment have implicated RA in antero-posterior patterning both along the body axis and in developing Limb bud.

and

Retinoic Acid receptors (RARs) are nuclear receptors related to the steroid and thyroid hormone Receptors, a family of proteins that function as ligand-dependent transcription factors.

RAR’s are not membrane receptors, but instead exist as proteins in the cytoplasm.

Insp. Bunny Interview Part 3

We’re back.  Inspector Bunny, you said that the SRP was an elegant system that would go on to influence evolution.  Can you expand on that?

Sure.  A key component of the SRP is one of the domains that is part of the RNA component, known as the Alu domain.  This Alu domain is not needed for life to exist, given the fact that most bacterial SRPs don’t have it.  But some do have it.  And interestingly enough, those bacterial versions of the SRP look more like the human Alu domain than other protozoan domains.  In other words, in some bacteria, the SRP is needlessly complex for survival, but appears to be needed for the subsequent evolution of more complex states.

How so?

Well, first of all, bacterial don’t need the Alu domain because they don’t need to pause ribosomal synthesis.  The cells are so small that they can hook up the ribosome to the membrane protein channel while the gene is in the very process of being expressed.  But in the much larger eukaryotic cell, whose cytoplasm is cut off from the DNA by the nuclear membrane, the pause function is needed. And it is the Alu domain that serves as the core component for delivering this pause function.  In other words, some bacteria contain an SRP that would function as one preadaptation that would nudge evolution toward the emergence of the eukaryotic cell, a cell plan that would be needed to evolve a complex animal state.

Oh, so you are saying the Alu domain that is part of the RNA component of the SRP is there to facilitate evolution?

Sure.  I’m saying we can perceive things like this and there is nothing to say we would be wrong.  From there, we would find example after example of other preadaptations, all converging on the same nudge.

Such as?

Oh, that is a whole set of other features found in various bacteria.  We’ll get to some of those eventually, but let’s instead notice that the SRP is apparently not finished in guiding subsequent evolution.

So you are saying there is more to the SRP story than being an elegant system that not only solves a core problem for life, but also facilitates the evolution of the complex eukaryotic state?

Well done, One with Glasses.  Billions of years after the origin of eukaryotes, fast-forward to the evolutionary emergence of primates.  If primates had not evolved, humans could not have evolved.  Something very interesting happened very early in primate evolution.  The sequence for the Alu domain was copied and duplicated and gave birth to a new retrotransposon – the Alu element.

What’s that?

Think of a retrotransposon as a device that can make copies of itself and spread throughout the entire genome.  If you are a duck, you’ll see it as some selfish parasite and yawn.  But we bunnies, while understanding how the ducks see it, also see a deeper meaning – it is a mechanism to reformat entire genomes.  That is, it is a mechanism to enhance and facilitate evolution.  Remember, the blind watchmaker is completely at the mercy of the variability that life hands it.  These Alu elements set about reshaping the genome, offering the blind watchmaker a vastly larger array of options to edit.  And during primate evolution, these Alu elements were busy trying out different reformatting solutions for brain development.

So the SRP then ultimately played a role in the evolution of the human brain?

Yeah, a big role.  In fact, without the Alu elements, he have no reason to think the human brain would have evolved.  What’s more, without retrotransposons, we have no reason to think the human brain could have evolved.

Earlier, I mentioned that all designers are constrained by the available design material.  Since the blind watchmaker is a designer-mimic, and its design material is largely protein, then we need to ask just what could the blind watchmaker actually make without proteins?  Would it still be able to produce a world like the one that exists?

Well, here we see the same theme, but in this case, it is not design material, it is design strategies that are available.  The Alu elements allow for the possibility of massive and relatively speedy reformatting and adaptation.  Could the blind watchmaker have sculpted something like a human brain without this mechanism being available?

I see.  So you are saying that the blind watchmaker will always do what the blind watchmaker does – cull available variability according to some fitness test.  But that because of the SRP, the blind watchmaker has more options to work with.

Sure.  What’s more, some of those options will always sit there in-waiting, knowing that sooner or later the blind watchmaker is bound to call upon them.  It’s just a matter of time.  And once called on, they can help steer and guide the blind watchmaker, causing something remarkable to emerge on the stage that in turn will add further guidance when it comes to future available options.

Y’see, this Alu story gets even more interesting.

Tell us.

Well, I’ve run out of time and need to return to all that inspecting right away.

Okay, Inspector Bunny.  Thanks for talking with us.  We’ll be sure to follow your next hare-brained installment.

Thank you.

This is all so dessspicable!