The spliceosome: a molecular machine that defies any non-design explanation.

_{Giuseppe Puccio

December 21, 2017

Intelligent Design}

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OK, let’s start with a very simple fact: eukaryotic genes have introns.

IOWs, they are not continuous. They are made of exons and introns: exon – intron – exon – intron – exon and so on. Exons code for the protein. Introns don’t.

So, when the content of the gene is copied to the mRNA, introns must be cut away, and only exons are retained, in order to be translated, so that the mature mRNA can be transferred to the cytoplasm and translated by the ribosome.

This process of removing introns is called splicing.

Now, a few clarifications:

a) Introns exist in prokaryotes too, but they are rather rare. For our purposes, we will only discuss introns in eukaryotes.

b) Introns exist in many different types of genes. For our purposes, we will discuss only those in protein coding genes.

c) The origin and possible function of introns is, still, a mystery.

d) Introns are usually longer than exons. In humans, for example, they amount to approximately 35% of the whole geneome, vs about 1.5% of coding exons.

e) However, the amount and length of introns can vary a lot in different organims. An extreme example is yeast (s. cerevisiae), whose genome contains a very small amount of introns (about 250 out of about 6250 genes).

When the gene if transcribed, both exons and introns are transcribed. A 5′ UTR (Untranslated region) and 3′ UTR, is also part of the pre-mRNA.

Fig. 1

Pre-mRNA is the first form of RNA created through transcription in protein synthesis. The pre-mRNA lacks structures that the messenger RNA (mRNA) requires. First all introns have to be removed from the transcribed RNA through a process known as splicing. Before the RNA is ready for export, a Poly(A)tail is added to the 3’ end of the RNA and a 5’ cap is added to the 5’ end. – By Nastypatty (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

So the question is: how are introns removed from pre-mRNA? IOWs, how is splicing achieved?

And there is more. As everybody probably knows, splicing is not always done in the same way. Different isoforms of the same protein can be obtained by alternative splicing, and they can have functional differences. I will not go into details about that, but here is the Wikipedia page about alternative splicing:

https://en.wikipedia.org/wiki/Alternative_splicing

So, how is splicing done, and how is alternative splicing regulated?

We know much about the first question, very little about the second.

There are three ways to perform splicing:

Spliceosomal splicing
Self-splicing
tRNA splicing

The last two modalities are rare, and can be found both in prokaryotes and eukaryotes. I will not discuss them here.

So, the subject of this OP is spliceosomal splicing, which is restricted to eukaryotes.

Moreover, I will discuss only the major spliceosome, which is responsible for the vast majority of splicing in eukaryotes. It must be said, however, that also a minor spliceosome exists, and that it acts in a minority of cases.

So, the spliceosome.

The first important point is:

It is an amazing molecular machine. Even more, it is an amazing molecular cycle, involving many different stages each of which is an amazing molecular machine.

Let’s see. Here is a figure which summarizes the main stages of the spliceosome cycle:

Fig. 2

Spliceosomal splicing cycle – By JBrain [CC BY-SA 2.0 de (https://creativecommons.org/licenses/by-sa/2.0/de/deed.en)], via Wikimedia Commons

To make it simple, the spliceosome units are built upon 5 specific RNAs, called small nuclear RNAs (snRNA). These are, in humans:

U1 (164 bases), U2 (187 bases), U4 (145 bases), U5 (116 bases), U6 (107 bases)

They are transcribed from multiple gene copies. While their sequences are not particularly conserved (U6 being the most conserved of all), their secondary structure seems to be very conserved.

snRNAs are very important in the spliceosome, because they seem to be responsible for the catalytic activities.

Each of the 5 snRNAs forms a complex with proteins, and the complex takes the name of snRNP. The whole spliceosome includes at least 145 different proteins, maybe more, some of which are still not well known.

I will mention here some of the most important:

U1 snRNP:

U1 snRNP 70 kDa (P08621, 437 AAs)

U1 snRNP A (P09012, 282 AAs)

U1 snRNP C (P09234, 159 AAs)

Sm proteins: 7 small proteins (76 – 240 AAs) which form the “Sm core” ring in spliceosome subunits U1, U2, U4, U5, a ring which hosts the specific snRNA molecule.

U2 snRNP:

U2 snRNP A’ (P09661, 255 AAs)

U2 snRNP B” (P08579, 225 AAs)

SF3a120 (Q15459, 793 AAs)

SF3a66 (Q15428, 464 AAs)

SF3a60 (Q12874, 501 AAs)

SF3b155 (O75533, 1304 AAs)

SF3b145 (Q13435, 895 AAs)

SF3b130 (Q15393, 1217 AAs)

SF3b49 (Q15427, 424 AAs)

SF3b14a/p14 (Q9Y3B4, 125 AAs)

SF3b10 (Q9BWJ5, 86 AAs)

Sm proteins

U4/U6 snRNP:

Prp3 (O43395, 683 AAs)

Prp31 (Q8WWY3, 499 AAs)

Prp4 (O43172, 522 AAs)

Cyph ( O43447, 177 AAs)

15.5 K (P55769, 128 AAs)

Sm proteins (for the U4 snRNA)

Lsm proteins: a number of proteins similar to Sm proteins (usually Lsm 2-8), which form a specific ring for the U6 snRNA.

U5 snRNP:

Prp8 (Q6P2Q9, 2335 AAs)

BRR2 (O75643, 2136 AAs)

Snu114 (Q15029, 972 AAs)

Prp6 (O94906, 941 AAs)

Prp28 (Q9BUQ8, 820 AAs)

52 K (O95400, 341 AAs)

40 K (Q96DI7, 357 AAs)

Sm proteins

Additional proteins in the U4/U6/U5 complex:

hSnu66 (O43290, 800 AAs)

hSad1 (Q53GS9, 565 AAs)

27 K (Q8WVK2, 155 AAs)

OK, these are only the main components, and the best understood. We are still far from the sum total of 145/150 proteins which are involved in the spliceosome cycle.

But how does it work?

Always in brief. Here is a typical exon-intron structure:

Fig. 3

Parts of an intron – By miguelferig (Own work) [Public domain], via Wikimedia Commons

GU, A and AG are nucleotides almost universally conserved in all introns, approximately at the positions shown in the figure, and which have a fundamental role in splicing. However, the real stuff is much more complex than this (see the splicing code section). GU (n. 4 in the figure) is near to the 5′ end of the intron, AG (n. 1) near to the 3′ end. The A (n. 3 in the figure) is called “the branch point”. The py-py-py (n. 2 in the figure) is the “polypyrimidine tract”.

a) The U1 subunit binds to the GU sequence at the 5′ splice site in the intron

b) The U2 subunit binds to the “branch point”.

c) The U4/U6/U5 binds to the complex.

d) Numeorus further modifications take place, causing the formation of a “lariat” (including the intron), which is then cleaved, while the two exons are ligated.

I will spare you the many complexities in all the various steps, which are well summarized (in a very simplified way) in this Wikipedia page:

RNA splicing

See in particular the “Formation and activity” section.

Or, if you like more detail, here:

Spliceosome Structure and Function

And here is a very good video on the whole splicing process in yeast:

Now, if somebody still has doubts about the complexity of this molecular machine/process, let’s consider some important aspects.

1. The spliceosome is a molecular machine which appears in eukaryotes.

I quote from this paper (in the abstract):

Origin and evolution of spliceosomal introns

There is no indication that any prokaryote has ever possessed a spliceosome or introns in protein-coding genes, other than relatively rare mobile self-splicing introns.

The following Table shows how some of the main proteins involved in the spliceosome activity show practically no trace of homology in prokaryotes. I have included also included in the table two examples which show low homologies due to some domain which is already expressed in prokaryotes: Prp4, whose 209 bits of homology are due to a specific domain, WD40, and Prp28, which exhibits 313 bits linked to the DEXDc domain. The point is: many of the spliceosome proteins are complete novelties in eukaryotes, but not all of them.

Protein	Bacteria	Archea
U1 snRNP 70 kDa (P08621, 437 AAs)	67	–
U2 SF3b130 (Q15393, 1217 AAs)	43.5	–
U4/U6 hPrp3 (O43395, 683 AAs)	–	–
U4/U6/U5 hSnu66 (O43290, 800 AAs)	–	–
U5 Prp8 (Q6P2Q9, 2335 AAs)	–	–
U5 Prp6 (O94906, 941 AAs)	100	–
U4/U6 hPrp4 (O43172, 522 AAs)	209	150
U/5 Prp28 (Q9BUQ8, 820 AAs)	313	286

I will analyze in more detail one of the most important proteins in the spliceosome, Prp8, in the last part of this OP

(Just a technical note: if you blast Prp8, you will find 3 hits which are obviously an error due to unverified sequences, probably cases of contamination).

2. The spliceosome is a molecular machine which is universally present in eukaryotes.

All eukaryotes have introns, even if in very different degrees, and the spliceosome, even if in some organisms parts of the spliceosome complex can be lost. For a more detailed discussion, look at the Rogozin paper quoted above (Origin and evolution of spliceosomal introns), in particular the section:

Intron density, size and distribution in protein coding genes across the eukaryote domain

I quote this important conclusion:

As pointed out above, despite the existence of numerous, diverse intron-poor genomes, eukaryotes do not lose the “last” intron or the spliceosome although degradation of the spliceosome including loss of many components does occur, e.g. in yeast. The only firmly established exception is the tiny genome of a nucleomorph (an extremely degraded intracellular symbiont of algae) that has lost both all the introns and the spliceosome [7]; preliminary genomic data indicate that all introns might have been lost also in a microsporidium, a highly degraded intracellular parasite distantly related to Fungi [54].

So, whe can conclude that both introns and the spliceosome are a universal feature of eukaryotes, the few exceptions being simply cases of loss of information.

3. The spliceosome is a molecular machine whose information is extremely conserved throughout eukaryotes, up to humans.

I have already mentioned that the 5 RNAs which form the core of the spliceosome are not extremely conserved at sequence level, even if they are extremely conserved at structure level.

However, many of the proteins that compose the spliceosome show an amazing sequence conservation throughout eukaryotes. Now, even if we cannot be certain of when eukaryoyes really emerged, and of their early evolutionary history (both issues being at present highly controversial), we can reasonably assume that protein sequences which are highly conserved in all eukaryotes have been conserved for something like 2 billion years (more or less). As anybody who has followed my previous OPs about information conservation in vertebrates certainly knows, that is an evolutionary time frame which certainly allows us to equal conservation to extremely high functional constraint.

But how conserved are spliceosome proteins? We can analyze a few of them with my usual methodology: looking at human conserved information. The results shows that many proteins involved in the spliceosome are amazingly conserved in all eukaryotes. While there are a few cases which have a rather different evolutionary history, this is by far the most common behaviour for spliceosomal proteins.

Here is a sample of some important sequences that show high homology with the human form in all major groups of single celled eukaryotes. The 5 groups of single celled organisms chosen here, indeed, cover rather well the whole range of single celled eukaryotes.

Fig. 4

These four important proteins, as shown, have an amazing amount of information shared with the human form, ranging from more than 1000 to more than 4000 bits. In bits per AA, the range goes from 0.88 to 1.80 bits per aminoacid (baa). As can be seen, the highest homology is found in fungi, as expected, because fungi are the most likely ancestors of metazoa. The lowest homologies are observed in Naegleria (Excavata) or in Alveolata.

Of course, these proteins remain highly similar to the human form in the following evolutionary history in Metazoa.

So, we can safely state that most spliceosomal proteins, while emerging almost entirely in eukaryotes and showing only trivial homologies with prokaryotes, were probably already universally present in the Last Universal Eukaryotic Ancestor (LECA), and in a form already very similar at sequence level to what we observe in metazoa and in humans.

4. The spliceosome is a wonderful example of irreducibly complexity.

OK, we have already said that splicing can be achieved in at least three different ways. For example, bacterial introns, although rare, are of the self-splicing type. So, we know that the generic function of splicing introns can be implemented in different ways.

But eukaryotic introns are of the spliceosomal type, and they are spliced only by the spliceosome.

We have also said that a minor spliceosome also exists. It shares some featues with the major spliceosome, but it is a different structure and acts on different, and much rarer, introns.

So, for the vast majority of eukaryotic introns, the major spliceosome, and only the major spliceosome, can effectively accomplish the splicing.

Now, I don’t mean here that the major spliceosome must always be absolutely complete, with all its 150 proteins, to be able to work. That’s not what I mean when I say that it is irreducibly complex.

Maybe in some organisms the spliceosome can be partially defective, and still work. It is difficult to say, because we still don’t understand the role of all the components of the spliceosome.

But however, as far as we can understand, most of the principal features must be present, because, as we have seen, the splicing is the result of a complex cycle, involving the RNAs and the subunits, and all stages are essential to the final result.

So, the spliceosome is certainly highly irreducibly complex, even if we may not be able to clearly identify the essential nucleus of molecules which is absolutely necessary to the minimal function.

Moreover, the spliceosome would be useless if spliceosomal introns did not exist, with their properties and code (see later), and spliceosomal introns could not exist if the spliceosome were not there to splice them, because otherwise transcription would be completely ineffective. So, in that sense, spliceosomal introns and the spliceosome are a good example of chicken egg paradox, or we could also say that they form an irreducibly complex system at a higher level. And remember, the whole system seems to have been already present, very much similar to its current form in humans, in LECA, as we have seen.

But, of course, our darwinist friends will simply say that they have co-evolved! 🙂

Moreover, we can and should ask ourselves: why is the spliceosome so complex? The answer is not easy, because we still understand very little, but it is certainly related to the complexity of the splicing code, and to the fundamental issue of alternative splicing.

The Splicing code.

To splice introns by localizing 5 (or a few more) conserved nucleotides and then cutting at the ends of a lariat and rejoining the two exons is certainly a complex task, but apparently not so complex that one of the biggest and most impressing known molecular machines is needed for that. But the simple truth is that recognizing and appropriately splicing all introns is a much more complex task than that.

That is due to the simple fact that conserved nucleotides at the ends are not a sufficient signal to identify the segment that has to be spliced, and that a lot of other components (not always well understood) are necessary to that, and that the splicing is not made always in the same way, and that alternative splicing is a very powerful tool for transcription regulation.

The subject is very complex, and I will not deal with it in depth. However, Those interested could look at this recent review:

The splicing code.

Unfortunately, the paper is paywalled, but the abstract is very informative.

The complexity of the splicing code can give us some insight about the true reasons for the complexity of the spliceosome, and definitely supposrts the idea that the whole system, introns, splicing code and spliceosome, is irreducibly complex.

The Prp8 protein.

I will add a few words about this proteins, which is probably the most amazing component of the spliceosome, and well represents its essential features.

This protein has many amazing charactertistics:

a) It is, as far as I can say, the longest protein in the whole spliceosomal system, and a very long protein indeed: 2335 AAs.

b) It is completely absent in prokaryotes.

c) It is extremely conserved in eukaryotes, probably the most conserved protein in the whole spliceosomal complex (see Fig. 4). In Naegleria, we have 3345 bits of homology with the human protein, corresponding to 1.4 baa, while in fungi we have the amazing result of 4211 bits of human-conserved information, corresponding to 1.8 baa. IOWs, in fungi we already find almost 90% of the functional information present in human Prp8 (remember, the highest possible bitscore is about 1.2 baas), corresponding to 1995 identities (86%) and 2155 positives (92%): a result which is incredibly rare, considering that such information has been conserved for about 2 billion years.

Just to emphasize the importance of this fact, here is the blast between the human protein and the best hit in fungi (Basidiobolus meristosporus):

d) It is a protein which is extremely important for the function of the spliceosome. Here is a very good paper about this protein and its functional relevance:

Prp8 protein: At the heart of the spliceosome

I quote from the conclusions:

Prp8p is central to the expression of all nuclear intron-containing mRNAs. In higher eukaryotes, it is responsible for processing thousands of transcripts in alternative splicing pathways, and in both U2 and U12 spliceosomes. It is important for the pathology of human disease, as all eukaryotic pathogens and parasites require Prp8p to functionally express their genes, in some cases via the trans-spliceosome. Retinitis Pigmentosa, a human genetic disorder that causes progressive blindness, positions Prp8p as a target for therapeutic medicine.

Moreover, another way to assess the functional constraints of a protein is to check its tolerance to polymorphisms in humans. That can be done consulting a very recent and useful database, the ExAC browser, which reports data from about 60000 human genomes.

ExAC gives two important metrics to assess how much a protein is tolerant to polymorphisms and variants. I quote here from the site FAQ:

What are the constraint metrics?

For synonymous and missense, we created a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer variants than expected. Negative Z scores are given to genes that had a more variants than expected.

For LoF, we assume that there are three classes of genes with respect to tolerance to LoF variation: null (where LoF variation is completely tolerated), recessive (where heterozygous LoFs are tolerated), and haploinsufficient (where heterozygous LoFs are not tolerated). We used the observed and expected variants counts to determine the probability that a given gene is extremely intolerant of loss-of-function variation (falls into the third category). The closer pLI is to one, the more LoF intolerant the gene appears to be. We consider pLI >= 0.9 as an extremely LoF intolerant set of genes.

Now, for Prp8 we get the following results:

Constraint from ExAC	Expected no. variants	Observed no. variants	Constraint Metric
Synonymous	366.6	460	z = -3.02
Missense	920.2	266	z = 10.55
LoF	92.6	8	pLI = 1.00

That means the following:

a) The number of observed missense variants is so low vs expected (266 vs 920.2) that the z value is 10.55 (IOWs, 10.55 standard deviations, more than 10 sigma). Believe me, this is a really exceptional result, most proteins are much more tolerant to missense variants.

b) The probability of loss of function is 1. That means that even heterozygous LoF is absolutely not tolerated.

This is an extremely functional molecule, if ever there was one!

A brief conclusion.

To sum up the meaning of this rather long discussion, I would simply say:

The introns – spliceosome system is a molecular machine of amazing complexity. I have touched only its main aspects in this OP, but believe me, there are layers of complexity there that would require a whole treatise and that I have not even started to mention here.
Whoever can really believe that all this can be explained by some RV + NS model is, IMO, really admirable for his faith in a wrong paradigm.

Comments

GP, Maybe they provide a necessary stepping stone for those of our enemies that weren't really our enemies after all. It may turn out that blindness is harder to sell when you can open your eyes.Upright BiPed_{January 6, 2018
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Dionisio, ET: The amazing thing with all these third way fans is that they seem not to realize that: a) The neo-darwinian model, as we all agree, cannot certainly explain functional complexity in biology by RV + NS (for details, see my OPs and following discussions here): https://uncommondescent.com/intelligent-design/what-are-the-limits-of-natural-selection-an-interesting-open-discussion-with-gordon-davisson/ https://uncommondescent.com/intelligent-design/what-are-the-limits-of-random-variation-a-simple-evaluation-of-the-probabilistic-resources-of-our-biological-world/ but b) If they try to put away, or even simply minimize, the role of NS, as those third way freaks seem so eager to do, they are left literally with nothing: no explanations at all, of anything. The probabilistic barriers that NS certainly cannot overcome become then absolute barriers, that they don't try to climb in any way, not even just going through the motions. So, design remains the only, solitary king of biological explanations. Are these third way guys our friends or our enemies? I really don't know. And, frankly, I don't like not to know. In the end, I probably prefer some honest and clear and consistent enemy, like Lewontin, or Dawkins, or Coyne! :)gpuccio_{January 6, 2018
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Dionisio: The EES site seems a good repository of general "third way" arguments. But where is it that they criticize Shapiro? They should be on a similar page with him, apparently!gpuccio_{January 6, 2018
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Dionisio: The Panda's Thumb piece is not even an article. It is just a political piece against "anti-science". In a very general sense, I agree. I am not anti-science at all. Frankly, I am somewhat annoyed when true anti-science arguments emerge in this blog (and sometimes they do), but I simply stay silent. Science is an important part of human cognition, and there is no reason to be against it, in any way. Scientism is a bad philosophy that tries to give to science the role of exclusive truth repository. As a bad philosophy of science, I deeply dislike scientism, and I believe that it is a truly anti-science view of reality, because it betrays the foundations themselves of good science. Science itself, of course, can be wrong. That's its precious privilege. When it is wrong, scientific arguments only can make it right. In the case of neo-darwinism, I am convinced that a deep cognitive bias has been working for decades, making biological science in our era strongly prejudiced in favour of a wrong and deeply bad scientific paradigm. That is a shame for science itself, and should be antagonized by all true lovers of scientific thought. That's what I try to do here, in my personal way. For the rest, I have no problems at all with science, including of course biology. And I am not interested in political fights about it, because again I believe that science should always be well above those planes.gpuccio_{January 6, 2018
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ET @282, Your comment seems to thicken the plot. :)Dionisio_{January 6, 2018
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ET @282, Interesting comment about the possible reasons behind Dr. Shapiro's buttering his bread on both sides. :) Thanks.Dionisio_{January 6, 2018
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gpuccio- It is my gut feeling that Dr James Shapiro was coerced into "natural genetic engineering that evolved via blind and mindless processes". Jerry Coyne probably had an office right down the hall from his and he couldn't allow a colleague to give away anything.ET_{January 5, 2018
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gpuccio, Did you look at the last two links provided by toza in that same thread? https://uncommondescent.com/evolution/self-organization-new-james-shapiro-paper-on-the-read-write-genome/#comment-647217 They seem to criticize Dr. Shapiro pretty harshly. Perhaps that's the price to pay for buttering his bread on both sides? :)Dionisio_{January 5, 2018
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@278:
the worst conservative neo-darwinian views turned very bad philosophy! Everything is there, from redefinition of function in neo-darwinian terms to the infamous Constructive Neutral Evolution!
A real treasure trove (of plain nonsense)! :)Dionisio_{January 5, 2018
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@277:
Natural Genetic Engineering! IOWs, design without a designer, engineering without an engineer. Which works… how?
Well, we should know by now: co-option! :)
What are the laws of nature that explain the “non random” activity of mobile elements?
Well, we should know by now: quantum physics! :)Dionisio_{January 5, 2018
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Dionisio: This paper that you referenced at #13 of the other thread: On causal roles and selected effects: our genome is mostly junk. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718017/pdf/12915_2017_Article_460.pdf is a very good summary of the worst conservative neo-darwinian views turned very bad philosophy! Everything is there, from redefinition of function in neo-darwinian terms to the infamous Constructive Neutral Evolution! Thank you for the link: it's very useful to have all the bad stuff together, in its most recent formulation. :)gpuccio_{January 5, 2018
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Dionisio: From: Living Organisms Author Their Read-Write Genomes in Evolution https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745447/pdf/biology-06-00042.pdf
The intersections of cell activities, biosphere interactions, horizontal DNA transfers, and non-random Read-Write genome modifications by natural genetic engineering provide a rich molecular and biological foundation for understanding how ecological disruptions can stimulate productive, often abrupt, evolutionary transformations.
Emphasis mine. In what sense "non random"? From section 7, where all the answers should be:
From these, and many other lines of molecular biology research, it has become abundantly clear that every genome is a densely formatted molecular database, syntactically organized to respond appropriately to the dynamic conditions of cellular life.
OK, it is "syntactically organized". 7.4:
By virtue of their abundance and the capacity to move throughout the genome, mobile DNA elements have specific properties necessary for rewiring and innovating transcriptional regulatory networks in evolution.
Emphasis mine. "Necessary", certainly! But "sufficient"? The following sections quote many interesting examples of how mobile elements are implied in both the regulation of regulatory elements and the synthesis on non coding RNAs implied in regulation.
A 2015 study of human embryonic stem cells (hESCs) identified fully 99.8% of the candidate human-specific transcription factor-binding sites within human-specific retrotransposable element-derived sequences, most notably LTR7/HERV-H, LTR5_Hs, and L1HS ... A 2017 analysis of 259 mouse embryonic cells at different stages from zygote to blastocyst reports enrichment of mobile DNA in expressed promoters and stage-specific utilization of different classes of mobile elements ... The placental tissue necessary for prenatal embryonic development depends on endogenous retroviruses for syncytial trophoblast development, as well as transcriptional programming. The essential “syncytin” proteins that fuse the cell membranes and provide an immune-protective barrier in the placenta are actually endogenous retroviral Env (envelope) proteins that are expressed from different ERV families in each mammalian order ... A 2015 article reports the utilization of evolutionarily ancient MER130 SINEs to form an integrated enhancer network for embryonic development of mouse dorsal neocortex ... A recent study in human cells identified 962 MER41 family primate-specific endogenous retroviral elements as binding sites for IFN-triggered transcription factors ... In Vesper bats, for example, over 61% of taxon-specific microRNAs can be traced back to mobile elements, largely from bat-specific DNA transposons [549]. Mobile DNA-derived microRNAs arise from lineage-specific transposition events [550,551] that can occur in bursts of genome innovation ... A 2012 analysis reported that 97% of human lncRNAs are primate-specific and found mobile DNA element sequences in 83% of 9241 human lncRNAs, where they constituted 42% of total lncRNA sequence
So, there can be no doubts that mobile elements are important for genome design and redesign. That rings a bell, doesn't it? No, wait a moment! Shapiro of course does not believe in design. At most, he believes in Natural Genetic Engineering! IOWs, design without a designer, engineering without an engineer. Which works... how? In all these (multiple) papers originated by Shapiro in a very short span of time, I have not found one single idea about explaining how mobile elements can do all that they do. Or why their activity is "non random". "Non random" can mean two things: designed, or caused by specific laws of nature. What are the laws of nature that explain the "non random" activity of mobile elements? I can find no mention of them in Shapiro's papers. Maybe because of course they do not exist. :) One last question: how can Shapiro originate so many different (OK, maybe not so different) papers at the same time? As one friend said here, does he even sleep? OK, probably they were simply originated by Natural Paper Writing, after all! :)gpuccio_{January 5, 2018
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gpuccio, Perhaps this paper is more recent: https://uncommondescent.com/evolution/self-organization-new-james-shapiro-paper-on-the-read-write-genome/#comment-647462Dionisio_{January 4, 2018
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gpuccio, Interesting 'random thoughts' on Shapiro's paper. You have dissected the paper and exposed its main contents. I think I see your point clearly. Thanks. I seems to me like the third way folks admit correctly that the neo-Darwinian theory doesn't explain everything coherently. But then they try to explain things in a convoluted way that elms to get lost in confusing statements that don't seem to make sense, as you noted. PS. IOWs, life has been constantly desinged! designed?Dionisio_{January 4, 2018
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Dionisio: Random thoughts while reading the Shapiro paper. I like how "third way" theorizers, like Shapiro, use words. Here is an example, just from the beginning of the paper:
The following sections present examples of these generic processes repeatedly achieving evolutionary innovations. These cases exemplify broader implications of biological agency (i.e. direct biochemical and biomechanical activity) in generating evolutionary variation:
"Broader implications of biological agency"??? What would that mean? Let's go on. Maybe we can understand better. Point 1.a is simple enough and clear enough. Horizontal transfer, symbiogenesis, hybridization. IOWs, information remixing. OK. Point 1.b is already on the mystical side: "cells have agency in generating organisms with new genome configurations" ?! "the genome functions as a read–write (RW) storage system in evolution" ? "The RW genome is subject to a range of generic inscriptions" !!! (is this a generic inscription?) and so on. I am a little bit lost here. But let's go on. Clarifications will certainly come. Point 1.c. Ah, here we come to "natural genetic engineering" (NGE). The meat, as you would say. But we don't learn much. The rather perplexing conclusion seems to be that:
By altering the regulatory context, one kind of genome-modification activity can stimulate other kinds in a positive feedback loop that amplifies evolutionary innovation.
Sounds good, doesn't it? Again, we will probably see real examples in the rest of the paper. Point 1.d seems an attempt to use the above information (which we still do not have) as "an empirical molecular–cellular basis for saltationist views of the evolutionary process, similar to those proposed by certain early evolutionists" (with references that range from 1894 to 2013). OK, this is just the premise. Section 2 is again about HGT, and again it is simple and clear: HGT is common, important, still working. OK, correct. Nothing really new. Section 3 is about symbiogenetic events. Nothing new here again, even if NGE is marginally called into action, without explanations:
Eukaryotic diversification thus resulted from biochemical NGE functions executing deletions, transfers and rearrangements of mitochondrial DNA.
Section 4 is about hybridizations and whole genome duplications. Information shuffling again. No special problems, but no special novelties. Section 5, of course, is "the meat":
Amplification of mobile DNA accompanies increased organismal complexity and provides information-rich cassettes for adaptive innovations
First, an important recognition of the role of mobile elements (ME):
All organisms contain repetitive DNA elements capable of transposing to novel genome locations [153]. Both transposition purely at the DNA level and retrotransposition through RNA intermediates tend to increase the copy number of a particular element, and MEs are collectively referred to as dispersed repetitive DNA.
Reaching levels of non coding DNA praise that would certainly be criticized by traditional neo darwinists, and are probably more compatible with our ID forum:
The class of mobile repetitive DNA has typically been considered functionally distinct from the relatively fixed, low copy DNA encoding the vast majority of organismal proteins. Hence, it was significant when the initial draft human genome sequence revealed that at least 44% of our genomes consisted of MEs [154]. (Today, our fraction of repetitive DNA is estimated to be as high as 67% [155].) In fact, the repetitive, so-called ‘non-coding’ content of the genome scales more closely with organismal complexity defined by the number of distinct cell types than does the protein-coding content, which plateaus in organisms of about a dozen different cell types [156]. In other words, MEs and other ‘non-coding’ sequences are especially prevalent in genomes of the most highly evolved organisms.
With reference 156 being, among others, the often execrated Mattick! The roles of mobile elements are many and important (I could not agree more!):
Focusing our attention on mammals, where the most in-depth genomic analysis has been performed, we can discern at least three major evolutionary roles for MEs [157]: (1)?MEs provide distributed signals, such as binding site for structural proteins and replication factors, to format the genome as a physically organized self-replicating sequence database [158–160]; (2)?Although characterized by some as non-functional ‘junk DNA’ [161,162], MEs provide cis-regulatory signals to rewire transcriptional networks determining multiple higher-level traits, including key mammalian innovations on both uterine and placental sides of the maternal–fetal interface in viviparous reproduction [163–166]; (3)?MEs provide the majority of conserved sequences comprising taxonomically specific ‘long non-coding lncRNAs' [167–169], a class of molecule that we increasingly recognize as modulating epigenetic control [170] and regulating complex traits like stem cell pluripotency [171–174], internal organ and nervous system development [175–177], and innate and adaptive immunity [178,179].
As said, I agree. Many times I have stated that ME are the most likely design tool, and that a lot of evidence supports their role in guided intelligent variation. Of course, Shapiro does not say anything about how ME should be able to do all that they apparently do. Magic, again? Section 6 is more a "conclusions" section. Here we learn that: 1) "These examples show us that core biological capacities for self-modification in response to ecological challenge have been integral to the history of life on earth." IOWs, life has been constantly designed! :) 2) "That conclusion should not surprise us" Well, maybe just a little... And the reason for that is: 3) "because extant organisms are descendants of multiple evolutionary episodes. " Wow! That's an explanation indeed! I repent of my surprise. 4) "Considering potential interactions between dynamic ecological conditions and the biological engines of cell and genome variation raises important questions about control and specificity in evolutionary innovation." OK. Important questions are always welcome. 5) "The years to come likely hold surprising lessons about how cell fusions, genome doublings, and natural genetic engineering may operate non-randomly to enhance the probabilities of evolutionary success." Standard "conclusion of conclusions", as everybody who has ever published a paper well knows! :) Maybe a little more word-refined than the usual: "further research is needed to clarify better many aspects of what we discussed here". But that's exactly what we expect from "third way" theorizers, as already said. :) I don't see in the paper much more than was in the abstract. Therefore, I am in no need to modify what I had already written at comment #2 here: https://uncommondescent.com/evolution/self-organization-new-james-shapiro-paper-on-the-read-write-genome/#comment-647217 in answer to J-Mac. His comment at #1 remains perfectly valid: "Seems obvious Shapiro has not problem to butter his bread on both sides…"gpuccio_{January 4, 2018
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Discussion between AH and GP Index of posted comments: AH @25 …….……. GP @28 AH @50 AH @51 …….……. GP @54 AH @56 * …….……. GP @60 …….……. GP @69 …….……. GP @75 …….……. GP @86 …….……. GP @98 …….……. GP @106 …….……. GP @118 …….……. GP @127 …….……. GP @129 AH @130 …….……. GP @136 …….……. GP @138 …….……. GP @146 …….……. GP @162 AH @164 …….……. GP @167 …….……. GP @176 …….……. GP @182 …….……. GP @198 …….……. GP @200 …….……. GP @201 …….……. GP @210 …….……. GP @211 …….……. GP @212 …….……. GP @231 …….……. GP @242 …….……. GP @253 ** …….……. GP @254 ** …….……. GP @263 …….……. GP @268 AH is the distinguished professor Arthur Hunt GP is the author of the excellent OP that started this discussion thread (*) first publicly admitted mistake @56 (**) not addressed to professor A. Hunt directly (to be continued…)Dionisio_{January 4, 2018
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@268:
[...] some irreducibly complex core of proteins is necessary for the spliceosomal function to take place. Probably, that core does not include all the 150+ proteins associated with the spliceosome, but it certainly includes a good number of them.
That's related to the OP. However, curiously professor Hunt's comments brought up a topic that led to this interesting analysis conclusion:
But we have, in our discussion here, an interesting and rather clear experimental demonstration of the irreducible complexity of another, simpler structure: the protein complex which effects the trans-splicing of psaA in Chlamydiomonas reinhardtii.
Dionisio_{January 4, 2018
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Any news from professor Hunt yet? :)Dionisio_{January 4, 2018
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@268:
So, we have a clear and experimental demonstration that the trans-splicing mechanism includes an irreducibly complex core of at least three different proteins (probably many more), whose mutation affects the trans-splicing in three different ways. Each of those three proteins is necessary for the function. The loss of any one of those three proteins causes the loss of function. That is irreducible complexity, I suppose.
Maybe not... :) A: Can a rectangular portable table stand alone on a tiled floor on three legs on the corners? B: of course! haven't seen it? A: but then no heavy objects can be placed near the corner that has no leg, right? B: perhaps... A: then the table can stand but is not fully functional and lacks stability B: well, but it stands, right? A: can it stand alone on just two legs? B: yes, attach the legless side of the table to a wall A: huh? B: you see? the four legs aren't necessary... even three legs aren't required A: but... B: no irreducible complexity! A: ok, whatever...Dionisio_{January 4, 2018
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gpuccio, Off topic: Last summer you wrote a very insightful comment on the abstract of a paper that was not for public access. It seems like the given paper is now open access. Somebody posted it in the same thread where you had written your comment: https://uncommondescent.com/evolution/self-organization-new-james-shapiro-paper-on-the-read-write-genome/#comment-647217Dionisio_{January 4, 2018
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Arthur Hunt (and all interested): Some further thoughts about Irreducible Complexity. I have already clarified that my idea is that some irreducibly complex core of proteins is necessary for the spliceosomal function to take place. Probably, that core does not include all the 150+ proteins associated with the spliceosome, but it certainly includes a good number of them. But we have, in our discussion here, an interesting and rather clear experimental demonstration of the irreducible complexity of another, simpler structure: the protein complex which effects the trans-splicing of psaA in Chlamydiomonas reinhardtii. Now, of course that structure is completely different from the spliceosome, and different is also its function, as I have discussed. But there is no doubt that it has been considered, by many, as an example of how a structure like the spliceosome can arise and work. So, a demonstration that the trans-splicing complex is irreducibly complex can be considered, in some way, as a strong suggestion that the spliceosome, which is certainly much more complex, is irreducibly complex too. But what is the experimental demonstration that the trans-splicing protein structure is irreducibly complex? Well, we can find it in the paper I have quoted: On the Complexity of Chloroplast RNA Metabolism: psaA Trans-splicing Can be Bypassed in Chlamydomonas https://academic.oup.com/mbe/article/31/10/2697/1013909 We know, from older papers, that at least 14 nucleus-encoded proteins have been associated, through mutant analysis, to the trans-splicing. Well, the 2014 paper uses, for the demonstration that trans-splicing can be bypassed by transformation with an intrnless gene, three different mutants: Raa1, Raa2, Raa3. Each of those three mutants derives from mutations in three different nuclear proteins. And each of the mutant is defective in photosynthesis, because of an ineffective trans-splicing of the psaA gene. Which is exactly the reason why they are used in the experiment. So, we have a clear and experimental demonstration that the trans-splicing mechanism includes an irreducibly complex core of at least three different proteins (probably many more), whose mutation affects the trans-splicing in three different ways. Each of those three proteins is necessary for the function. The loss of any one of those three proteins causes the loss of function. That is irreducible complexity, I suppose.gpuccio_{January 4, 2018
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GPuccio, Perhaps you have experienced otherwise, but I have learned that materialists, without exception, always "succeed" in misunderstanding my arguments.Origenes_{January 3, 2018
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Origenes: "If I understand you correctly, you meant “the essential nucleus of molecules” in a very abstract way. You were not talking about the physical heart / core of the spliceosome. You are talking about parts which are essential for the system to function, wherever they are." Yes, you understand me very correctly. :) Your exegesis of Arthur Hunt's statements is very interesting, but of course I cannot speak for him. :) Happy new year to you.gpuccio_{January 2, 2018
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Discussion between AH and GP Index of posted comments: AH @25 …….……. GP @28 AH @50 AH @51 …….……. GP @54 AH @56 * …….……. GP @60 …….……. GP @69 …….……. GP @75 …….……. GP @86 …….……. GP @98 …….……. GP @106 …….……. GP @118 …….……. GP @127 …….……. GP @129 AH @130 …….……. GP @136 …….……. GP @138 …….……. GP @146 …….……. GP @162 AH @164 …….……. GP @167 …….……. GP @176 …….……. GP @182 …….……. GP @198 …….……. GP @200 …….……. GP @201 …….……. GP @210 …….……. GP @211 …….……. GP @212 …….……. GP @231 …….……. GP @242 …….……. GP @253 ** …….……. GP @254 ** …….……. GP @263 AH is the distinguished professor Arthur Hunt GP is the author of the excellent OP that started this discussion thread (*) first publicly admitted mistake @56 (**) not addressed to professor A. Hunt directly (to be continued…)Dionisio_{January 2, 2018
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GPuccio, It seems to me that Arthur Hunt misinterpreted the following sentence from the OP:
GPuccio: So, the spliceosome is certainly highly irreducibly complex, even if we may not be able to clearly identify the essential nucleus of molecules which is absolutely necessary to the minimal function.
If I understand you correctly, you meant "the essential nucleus of molecules" in a very abstract way. You were not talking about the physical heart / core of the spliceosome. You are talking about parts which are essential for the system to function, wherever they are. I think Arthur Hunt read: GPuccio doesn’t know what molecules are at the heart of the spliceosome (but I do) and he says that irreducible complexity depends on these molecules, or something ... whatever he means. If I am correct that would explain:
A. Hunt: You did not mention the single most important thing about the spliceosome and splicing.
Translation: you don't know what is at the nucleus (heart) of the spliceosome, so you didn't mention it.
Hunt: Of course, I was referring to the fact that the spliceosome is a ribozyme. At the heart of the splicesosome sits what is essentially a self-splicing intron.
Translation: You could not “clearly identify the essential nucleus of molecules”, right? Well, I did it for you: a self-splicing intron.
Hunt: I think that the fact that the spliceosome is at its core a catalytic RNA calls into question assertions about the irreducible complexity of the complex. For reasons I hope are obvious.
Translation: Irreducibility was somehow connected to identifying the essential nucleus, right? Well now that you know that it is a self-splicing intron, well, … this “calls into question assertions about the irreducible complexity of the complex. For reasons I hope are obvious.”. Uh … maybe obvious if you misinterpret the OP. - - - - happy new year allOrigenes_{January 2, 2018
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Arthur Hunt (and all interested): While we wait for some possible new intervention by Arthur Hunt, I would like, just for the sake of completeness, to propose a few reflections about the points he has already made, in the measure that I can understand them. I will start with what he said at post #51:
I will add one thing to stir the pot. I think that the fact that the spliceosome is at its core a catalytic RNA calls into question assertions about the irreducible complexity of the complex. For reasons I hope are obvious.
Not so obvious maybe. At #54. I have already made some clarifications about the irreducible complexity of the spliceosome: "As you can see, I am not denying in any way that splicing can be performed by simpler and different structures. I also explicitly quote here self-splicing introns as an example of a different way to achieve splicing. My point is that the whole system which implements splicing for eukaryotic spliceosomal introns is a new and different entity, and that it is irreducibly complex. I have also specified that I don’t mean by that that all the components of the system are indispensable to achieve the function. But it is difficult to deny that some important irreducible core must be present to implement all the subtle and necessary aspects of eukaryotic splicing in most of eukaryotic genes." Now, for greater clarity, I would like to add the following concept: The possible irreducible complexity must be evaluated in reference to the true general function in the spliceosome complex. Of course the simple catalytic activity can be implemented by the RNA core, as we can see in group II self-splicing introns. But the role of the spliceosome is to effect the splicing in all the different spliceosomal introns that are found in the eukaryotic nuclear genome, and to do that in accord with the regulatory networks implied in alternative splicing. To do that, it certainly needs a robust protein structure, which may not imply all of the 150+ proteins as an irreducible core, but certainly implies a good number of them, which are as far as we know absolutely necessary to achieve the spliceosomal function as described. So, if we define correctly its important function, the spliceosome is IMO highly ireducibly complex. Arthur Hunt also says (at v#56):
As far as the proteins of the spliceosome are concerned, I guess if totally unrelated proteins in prokaryotic systems can also facilitate the activity of the core of the splicing enzyme, then maybe the uniqueness of proteins that make up these complexes is not so great as you are asserting.
I am not sure of what he means here by "uniqueness". The "totally unrelated proteins in prokaryotic systems" that "can also facilitate the activity of the core of the splicing enzyme" should be either the individual IEPs that stabilize the catalytic RNA in group II introns in prokaryotes, or the nuclear proteins that assist in cis or trans splicing of degenerate goup II introns in plant organelles. It seems that Arthur Hunt's reasoning, here, is more or less the following (my interpretation, of course): "The catalytic RNA core needs protein assistance in different scenarios. As different, and completely unrelated, proteins can assist the catalysis in different situations, then we can say that assisting the catalysis is a rather easy function to implement, even with very different proteins. Therefore, those proteins cannot have such a high functional specificity as you seem to believe." That the proteins are very different there can be no doubt. We have seen in detail that the proteins that assist catalysis in psaA trans-splicing, for example, are totally unrelated to spliceosomal proteins. Indeed, they are mainly totally unrelated to anything else, as we have seen. But what does that mean? Again, the two functions that we are observing are very different, even if they both are related to the catalytic splicing of introns. In the case of psaA, the function is extremely specific for one, and only one, situation: a very important gene that is fragmented, introns that are fragmented, some needful information that must be reconstructed and appropriately spliced. It is really amazing that a whole system of many proteins is necessary to accomplish one such specific task, but that is what we observe (at least with the information we have at present). Taxonomically restricted and complex proteins implement the task, maybe only that task. But the spliceosome does something very different. It is an universal and flexible machine, which incorporates the RNA catalytic core so that it can be applied to all spliceosomal introns, and possibly in such a way that all regulatory networks linked to alternative splicing may be implemented too. It is universal cellular machine, like the ribosome. Is it so surprising that the proteins in the spliceosome are so many, and that they are completely unrelated to the proteins in psaA trans-splicing? The functions are really different, so the proteins that implement them are dramatically different. That's exactly what we should expect, in terms of functional information. But there is more. In the case of psaA trans-splicing, even if nobody really doubts of the complexity in the system, there are two problems which at present prevent us from quantifying realistically the functional information implied: 1) The molecular mechanism is still poorly understood 2) The proteins are not conserved in other organisms, indeed they do not exist in other organisms, and so it is impossible to use evolutionary conservation as a measure of functional complexity. IOWs, we are rather sure that Raa1, for example, must be complex in its function (how can we doubt that for a protein of 2000+ AAs), but we cannot really measure, even approximately, that functional complexity. But in the case of the spliceosome, things are very different. Proteins are universal and extremely conserved. For very long evolutionary periods. We have seen that for Prp8 we can assess a functional information of the order of 3000 - 4000 bits. Even Chamydomonas reinhardtii Prp8 has about 4000 bits of homology with humans. That is, I would say, an undeniable evidence of its huge functional information and specificity, IOWs of how "unique" this protein is. Of course, Arthur Hunt also says, in post #164:
I will in due time turn to the matter of the proteins that participate in the splicing of group II introns and of introns that are substrates of the spliceosome. I will mention at this time, though, one thing that gpuccio needs to consider. This is that it is not appropriate to rely solely on BLAST, either to understand distant evolutionary relationships or to assess information content. At least in the sense laid out by Dembski many years ago. Some of the subunits of the complex I work on defy the logic being used here. I mention this because it will factor in to my further comments.
As I have said, I use BLAST to assess functional information in proteins conserved for long evolutionary periods. The only assumption here is that such a conservation can only be explained by strong functional restraints, and therefore by a strong effect of negative, purifying selection. That is, as far as I can understand, in perfect accord with the basics of neo-darwinian theory. "To understand distant evolutionary relationships" and "to assess information content" are two very different tasks. In the first, one can be interested in higher sensitivity to detect very low similarities. Tools like Psi-blast can be appropriate for that. From the NCBI site: "PSI-BLAST provides a means of detecting distant relationships between proteins" But for an ID analysis, we are not interested in distant relationships, or in low similarities. We are interested in strong sequence conservation, which can be evidence for undeniable functional constraint. In that sense, ID tools must privilege specificity, not sensitivity. We need to reduce or eliminate false positives, and for that we will tolerate false negatives. That's why Blast is an appropriate tool. When we find a very high homology between proteins by Blast, especially if in the range of hundreds or thousands of bits, we can be certain that such an homology is absolutely real, and cannot be explained by chance. And if that homology has survived hundreds of million years of evolutionary time, negative selection is the only possible explanation. I am not sure of the meaning of the Dembski reference. Finally, I am really interested in the "subunits of the complex" Arthur Hunt works on, to understand why and how they "defy the logic being used here". But for that, I suppose that I really need his help! :)gpuccio_{January 2, 2018
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We haven't heard from professor Arthur Hunt since last year. :)Dionisio_{January 1, 2018
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gpuccio, Yes, that's a valid explanation within the neo-Darwinian "anyway, whatever (somehow)" paradigm. :)Dionisio_{December 30, 2017
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Dionisio: Don't be fastidious! After all any gene could be disrupted. The rescue mechanism seems to be intron specific, so we only need a specific rescue for each possible intron fragment. And, as a few proteins are needed for each intron, we just have to multiply that for... 5? 10? But there's no problem at all. We can rely on a "pool" of RNA binding proteins, ready for all situations. How many? Thousands? Millions? Billions? Who knows?gpuccio_{December 30, 2017
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gpuccio @254: "And the organism cannot reasonably avoid strong negative selection, is the gene does not work." is the gene does not work. if the gene does not work? is - if?
How can any pre-existing structure be “ready” to assist some gene if it is randomly fragmented?
Well, that's a good question. But maybe the structure somehow evolved to be flexible enough to adapt to different situations, including random fragmentations of genes? Can you think of another option? :)Dionisio_{December 30, 2017
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The Splicing code.

The Prp8 protein.

What are the constraint metrics?

A brief conclusion.

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