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
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
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
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:
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:
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.
Excellent. Thank you
Thank you, gpuccio.
What a peasant surprise to find this OP here today!
Such a fundamental topic of biology explained by the best teacher in town.
Mile grazie!!!
mike1962, Truth Will Set You Free, Dionisio:
Thank you for your kind words! They are always deeply appreciated. 🙂
No additional comments needed.
From the abstract of the pay-walled paper “The Splicing Code” referenced in the OP:
gpuccio:
Another chicken egg conundrum?
Here’s a point where we may disagree:
“our darwinist friends will simply say that they have co-evolved”
Well, that statement left out an important term with strong explanatory power that they use in their [pseudo] scientific conclusions: ‘somehow’.
A more accurate sentence would read thus:
“our darwinist friends will simply say that they have somehow co-evolved”. 🙂
BTW, does the term “co-evolved” imply convergent evolution or those are unrelated concepts?
@7 follow-up
Off topic – quick digression
Is the RNA polymerase associated with another apparent chicken egg paradox too?
Just curious.
Thanks
Dionisio:
“our darwinist friends will simply say that they have somehow co-evolved”.
Glad to accept the correction. You are a better darwinian exegete than I am! 🙂
Here are a few papers perhaps related to the interesting discussion that is about to start here?
Intronic Splicing Enhancers, Cognate Splicing Factors and Context Dependent Regulation Rules
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753194/pdf/nihms399453.pdf
SR Proteins: Binders, Regulators, and Connectors of RNA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303883/pdf/molce-40-1-1.pdf
Directional Phosphorylation and Nuclear Transport of the Splicing Factor SRSF1 Is Regulated by an RNA Recognition Motif†
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884534/pdf/nihms782152.pdf
RNA and Proteins: Mutual Respect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373437/pdf/f1000research-6-11393.pdf
Major hnRNP proteins act as general TDP-43 functional modifiers both in Drosophila and human neuronal cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570092/pdf/gkx477.pdf
AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105168/pdf/ncomms13347.pdf
A-kinase anchoring protein AKAP95 is a novel regulator of ribosomal RNA synthesis
http://onlinelibrary.wiley.com.....13630/epdf
gpuccio @9:
I knew you’ll accept the correction, because that term may help to clarify the meaning of the sentence… or so they hope. 🙂
BTW, I left out other important terms they use quite frequently in the recent research papers: surprisingly, unexpectedly, etc. 🙂
@10 follow-up
Chtop (Chromatin target of Prmt1) auto-regulates its expression level via intron retention and nonsense-mediated decay of its own mRNA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175361/pdf/gkw831.pdf
TDP-43 stabilises the processing intermediates of mitochondrial transcripts
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550480/pdf/41598_2017_Article_6953.pdf
Differential alternative splicing coupled to nonsense-mediated decay of mRNA ensures dietary restriction-induced longevity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563511/pdf/41467_2017_Article_370.pdf
The fitness cost of mis-splicing is the main determinant of alternative splicing patterns
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663052/pdf/13059_2017_Article_1344.pdf
RNAs: dynamic and mutable
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708131/pdf/13059_2017_Article_1361.pdf
Intron retention enhances gene regulatory complexity in vertebrates
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688624/pdf/13059_2017_Article_1339.pdf
IRFinder: assessing the impact of intron retention on mammalian gene expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353968/pdf/13059_2017_Article_1184.pdf
Is there a main item #2 ?
Is it (2) The Splicing code. ?
(3) The Prp8 protein. ?
Dionisio:
You are right, as always: I had lost control of my listing hierarchy. Maybe my OPs are becoming too long! 🙂
So, let’s say that I cut the first 1., and leave the last two sections as added sections, and not parts of a list.
Next time I will try to be more careful… 🙂
Dionisio:
You provide a true treasure trove of papers about RNA-protein interaction, and the incredible multitude of factors involved in splicing regulation.
The spliceosome is probably the common agent which regulates all final effects at the end of such a complex, and still poorly understood, network of fine interactions.
DNA motifs, trans-acting proteins, RNA-protein complexes, all seem to have a vast and intricate role in this huge skein of parallel events that takes place in the nucleus and influences the final events of splicing and translation, that we often consider as simple outcomes of transcription.
Alternative splicing and its regulation are really black holes in our understanding of how cells work. A fascinating world, which we can add to the already stimulating and frustrating complexities of epigenetic regulation, of transcription factor networks, of chromatin states control, and, why not?, of morphogen gradients formation and regulation! 🙂
And I apologize for all that I am forgetting…
gpuccio,
The OP couldn’t be better in substance. It’s very insightful (I call it juicy!). Highly informative. Well structured.
Just one minor detail, which you just mentioned.
The first 1. wasn’t necessary.
As you know, I look at your papers very seriously.
Dionisio:
“As you know, I look at your papers very seriously.”
I know. You are my best editor. 🙂
All this congratulatory back-slapping makes me sick. I predict gpuccio will eventually run from this thread like he ran from the last one.
Apart from that. Good to see you again gpuccio.
Is that because introns in prokaryotes are self-splcing? We don’t need no stinking spliceosome.
How many random accidents did it take to cobble all that together Mr. Dawkins?
I was just reading up on that including alternative splicing, dual coding genes and duons.
If someone says these were not designed, no miracle will persuade him…Amazingly clever designs in DNA…
Great job gpuccio!
Mung,
Anything is possible when one is delusional, as are Dawkins and his followers…
Mung @19:
Perhaps we don’t know exactly how many, but it could have been a few changes here and there…despacito, until the whole thing worked, as it’s commonly done in the Boeing assembly facilities.
You may want to look at the evo-devo Despacito thread to see how simple that is.
🙂
Mung:
“Is that because introns in prokaryotes are self-splcing? We don’t need no stinking spliceosome.”
Yes! Introns in prokaryotes are rare and self-splicing.
No stinking slpiceosome needed, at all! 🙂
J-Mac:
Indeed!
Sometimes I am really amazed at the unending layers of new complexity that open themselves almost daily in biology. That seems never to end.
I hope some day people will awake from their strange hypnosis, and realize what should already be obvious and self-evident to all: the wonderful, thrilling amount of intelligence and design in the biological world.
Hi gpuccio,
You did not mention the single most important thing about the spliceosome and splicing.
The spliceosome along with chromosome structure and the nuclear pore complex makes the eukaryotic cell one of natures most spectacular origin events.
Not quite off topic is the question of Darwinists’ possibility given enough time …
Just this day I was questioning a maths expert and asked him “if they ask you -but it IS possible to accept A=B? – what is your reply?
“Certainly it is theoretically possible, but to ACCEPT that possibility which is one in a hundred you would have to dismiss the fact that the odds are 99 to 1 that A does not equal B, and you would have to give a convincing reason for rejecting.”
Arthur Hunt:
“You did not mention the single most important thing about the spliceosome and splicing.”
Hi, Arthur Hunt, welcome to the discussion.
Should I ask what it is?
bill cole:
Yes, the nuclear pore complex is another amazing example.
Really a simple thing, the transition to eukaryotes! 🙂
Belfast:
“Not quite off topic is the question of Darwinists’ possibility given enough time …”
I suppose the discussion here:
https://uncommondescent.com/intelligent-design/what-are-the-limits-of-natural-selection-an-interesting-open-discussion-with-gordon-davisson/
and here:
https://uncommondescent.com/intelligent-design/what-are-the-limits-of-random-variation-a-simple-evaluation-of-the-probabilistic-resources-of-our-biological-world/
could be of some relevance.
@12 follow-up
Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424149/pdf/ncomms15134.pdf
The intron in centromeric noncoding RNA facilitates RNAi-mediated formation of heterochromatin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322907/pdf/pgen.1006606.pdf
A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoietin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737145/pdf/gkv1168.pdf
Mechanisms and Regulation of Alternative Pre-mRNA Splicing
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526142/pdf/nihms710140.pdf
A mechanism underlying position-specific regulation of alternative splicing
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716086/pdf/gkx901.pdf
Arthur Hunt:
Yes, he did- it is in the title. 😎
Perhaps Art is talking about alternative splicing- something else blind and mindless processes don’t have an answer for:
From Uncovering the Spliceosomes’ secrets
But you did mention that- alternative splicing- in your OP…
ET:
I think Arthur Hunt should clarify his thoughts himself. If he likes, of course.
I will not try to guess, even if I have some idea…
Yes, normally I would agree, however this is Arthur Hunt we are talking about. He wants to refute your claim by showing you don’t know what the single most important thing about spliceosomes and splicing is. Cuz if you don’t know that then your argument fails cuz you don’t know jack about it.
Arthur Hunt:
I am always eager to learn.
What is the single most important thing about the spliceosome and splicing?
gpuccio,
Excellent work highlighting this incredible system.
But everyone knows such a functionally-complex, information-rich, integrated system could only come about through a long series of accidental particle interactions. Yeah, that’s the ticket . . . 🙂
—–
Thanks for taking time to lay out the details. Great resource.
@3 correction
Someone pointed to this error:
“peasant surprise”?
Well, I have no idea what that could mean.
It was supposed to read ‘pleasant surprise’ instead.
My typo.
Dionisio:
“Peasant surprise” = the simple, sincere and unadulterated surprise that a true peasant feels daily in front of the wonders of nature.
You are always very creative with your typos! 🙂
ET:
“Yes, normally I would agree, however this is Arthur Hunt we are talking about.”
Yes, it is Arthur Hunt. I know.
I should probably be happy that he has found time to read my OP, even to comment here, however briefly.
In a sense, I am.
But in another sense, a very important sense for me, I stick to a principle that has always guided me in all my discussions here. Here, in this blog which is intended to discuss science, all are equals, in the sense that all are important (or no important) for what they say, not for who they are.
That is in no way a lack of respect for scientific expertise, or for academic role. I fully respect all those things.
But, in a scientific debate, only ideas are important.
So, if Arthur Hunt (or anyone else) wants to “refute” my claims by a single unsupported statement, he is of course perfectly entitled to do that.
And I am perfectly entitled not to worry about that.
But, as I have said, I will not debate my imaginary guess of what he would say. I like discussion, but not unilateral discussion.
I really hope that Arthur Hunt will find the time, or the motivation, to make his statement a little more “explicit”. But that’s completely up to him.
Eric Anderson:
“Excellent work highlighting this incredible system.”
Thank you! And you are right, the system is really incredible.
“Thanks for taking time to lay out the details.”
They say that the devil is in the details. Isn’t it strange that nobody seems to wonder about the incredible amount of conserved information in proteins like Prp8, for example? And that the transition from prokaryotes to eukaryotes is still “explained” mainly as an endosymbiosis event (which could at best partially explain the origin of mithocondria and chloroplasts), while nobody seems too worried about the amazing informational novelty implied by structures like the spliceosome, the nuclear pore, and many others?
In this case, details are simply the truth that nobody wants to consider.
ET:
Here is another interesting passage from the page you linked at your #33:
@25:
What kind of mysteriously convoluted way to say something?
Melodrama, tragicomedy, psychodrama?
Not sure.
🙂
Arthur Hunt is very involved with plant t-RNA, and maize mitochondria. So, therein must lie the “most important thing about the spliceosome and splicing.”
I suspect his ideas run along these lines.
gpuccio @41:
“They say that the devil is in the details.”
Yep. And the failure to look at the details is critical to the evolutionary story.
The impression of evolutionary theory’s explanatory power is inversely proportional to the specificity of the discussion.
PaV:
I know that Artur Hunt is very involved in those issues, and he is certainly a great expert about RNA in general.
However, the page you linked seems to be about self-splicing introns, that I have explicitly not discussed in my OP, and that do not require the spliceosome.
Eric Anderson:
“The impression of evolutionary theory’s explanatory power is inversely proportional to the specificity of the discussion.”
Definitely!
I must say that i find very little explanatory power in it even at very generic levels, but certainly as soon as we start to deal with details even that vague illusion of credibility soon disappears! 🙂
It seems to me that the spliceosome is something that was simply cobbled together by evolution. It certainly doesn’t look like something put together by an intelligent designer.
gpuccio:
This might be what he thinks you’re overlooking: i.e., that the spliceosome can simply be viewed as a ‘part’ of an ‘intron.’
Whether a Ferrari is stored in your garage, or is found in the dealer’s showroom, doesn’t affect the presence of design one wit.
Hi all,
Thanks for your patience, and for the discussion. Always interesting to see how others view these things.
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. I know the subjiect of self-splicing introns is discouraged in this discussion, but it seems odd to me to rule as off limits the heart of the matter, as it were.
I should point out that I am simplifying this somewhat, to encourage discussion and research. I apologize if this is not kosher (in a manner of speaking).
I won’t be able to do a running discussion but I will check in periodically to answer questions and maybe move things along.
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.
The software product that my former employer successfully sold to many design engineering organizations, was in its core simply a bunch of bits and bytes somehow put together.
That’s all. Nothing really special about it that could classify it as the product of an intelligent mind.
That would be utterly ridiculous, to say it nicely.
🙂
Things like this:
https://www.kodugamelab.com/
are just a bunch of bits and bytes somehow put together. Pure physics.
That’s all. Nothing really special about it that could classify it as the product of an intelligent mind.
That would be utterly ridiculous, to say it nicely.
🙂
Arthur Hunt:
Thank you for the clarification.
A few quick thoughts about that point. I will probably come back more in detail tomorrow.
1) In my OP, I say:
So, I would not say that I “did not mention the single most important thing about the spliceosome and splicing.” I did mention very clearly that the catalytic activity in the spliceosome seems to be mainly due to the RNA component.
You say:
“I know the subject of self-splicing introns is discouraged in this discussion, but it seems odd to me to rule as off limits the heart of the matter, as it were.”
But that is not true at all. My intention has never been to discourage anything in this discussion. For the sake of simplicity, I have restricted my discussion in the OP to the major spliceosome, because I believed that the OP was long and complex enough that way. But of course I am very interested in any aspect of the issue in the discussion here. So, your comments are absolutely welcome.
Of course, you say something more, beyond the simple fact that the spliceosome is a ribozyme (at least in part). You also say:
“At the heart of the splicesosome sits what is essentially a self-splicing intron.”
Now, I have nothing against that concept, but as I had not the time to deepen this aspect, I would like to profit of your knowledge, and I ask you: is there evidence that the snRNAs in the spliceosome are derived from, or anyway similar to, self-splicing introns components?
Again, I have no problems in admitting that the RNA part of the major spliceosome can be derived from self-splicing introns, but I would like to know if there is evidence of that, at sequence level or at structure level.
However, even if that is true, you can certainly see that my discussion in the OP is mainly focused on the protein component of the major spliceosome. That is essentially the information component that I have tried to analyze.
So, even if the RNA part can be traced to something that already existed in prokaryotes, my discussion about the protein part remains, IMO, completely valid.
There can also be no doubt, IMO, that the eukaryotic spliceosome has a functional complexity that is completely different from that of self-splicing introns. That is what I am debating here.
Regarding irreducible complexity, I invite you to read again what I wrote in the OP:
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.
I hope that this helps to clarify my views. I am certainly looking forward to further contributions from you. As I have said, I do love discussion.
My questions @43 remain unanswered.
But now, it seems like @25 was barking up the wrong tree?
🙂
gpuccio,
Sorry that I overlooked your description. I need to read more slowly. Many apologies.
There is indeed an abundance of evidence for the proposition that the structural and catalytic components of the spliceosome and group 2 introns are basically the same. I suspect (but haven’t tried to check it out) that google will help you track this down.
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.
Reading more slowly won’t fix the “overlooking” problem. Paying attention to the words might help.
It seems like I’m not alone in the poor reading comprehension club. 🙂
BTW, the suspicion @55 was valid.
gpucio,
Another wonderful post! It’s so enjoyable and stimulating to read you.
A brief comment on the chicken and egg paradox regarding spliceosome introns and the spliceosome that you mention in section 4. We all know that biology offers a myriad of examples of such paradoxes. But these paradoxes are intractable paradoxes only in the context of naturalism. Open the door to a mind/intelligent agent and these paradoxes vanishes immediately for intelligent agents have this unique power to design and implement systems having the appearence of a chicken egg paradox.
gilthill:
Thank you for your kind words.
Of course a global design can explain that kind of logical dependencies. If a new plan is conceived as such, as a whole, and then implemented, even if in steps, then all different parts can be implemented at the same level of efficiency. We can have different implementations for similar functions, with different levels of complexity, but in each plan the different parts (which build up the irreducible complexity of the whole) will be harmoniously present.
I think I will go into greater detail about that in my answers to Arthur Hunt (as soon as I find a little time! 🙂 )
Arthur Hunt:
“Sorry that I overlooked your description.”
Thank you for the acknowledgement. It is appreciated.
Good to hear from you. I will soon answer your interesting points, but some further research is appropriate for that, so it could take a little time.
Not too much, I hope! 🙂
Dionisio:
“It seems like I’m not alone in the poor reading comprehension club.”
We have all been in that club, from time to time!
Arthur Hunt:
Hi Art, Thanks for your reply.
Are you seriously proposing that if we remove the catalytic RNA at the core of the spliceosomal complex that the remainder of the complex would continue to perform the same function, iow, that the catalytic RNA is superfluous?
Mung:
No, it would seem that he is proposing the opposite, that the proteins are not so essential. Or at least not so “unique”.
I will try to write a more detailed answer about that.
gpuccio:
So you think that he is proposing that the proteins are superflous to the function of the spliceosome complex, remove them all and everything would still work like before?
I have another hypothesis: that Art doesn’t understand what it means to say a molecular machine is irreducibly complex. After all these years.
Arthur Hunt @50:
Thanks for sharing some more information about the spliceosome. I had a question about this statement:
1. Are you saying the intron splices itself out of the sequence?
2. What does an intron in the “heart of the spliceosome” have to do with removing the introns in the relevant sequences?
3. I presume you aren’t suggesting that introns in genes are self-splicing?
Thanks for any further clarification you can offer.
Eric Anderson:
Self-splicing introns are self-splicing. Spliceosomal introns (the vast majority of introns in eukaryotes) are not.
I will try to add some details about these issues in my next posts.
…it became clear that one kind of intron (the spliceosomal introns), as well as the cellular machinery that removes them (the spliceosome), are ubiquitous in eukaryotic genomes.
– The Origin and Evolution of Eukaryotes. p. 295.
..spliceosomal introns appeared abruptly at the time of the origin of eukaryotes (and thus are quite ancient even if not primordial), and originated from preexisting self-splicing introns, which were likely present at very early stages of life.
– The Origin and Evolution of Eukaryotes. p. 296.
Personally I think they are primordial and not just ancient.
Arthur Hunt (and all interested):
So, I will start from your #56, and try to clarify my views on the issues you have mentioned.
I apologize in advance because I will have to clarify many aspects that you certainly know better than me. I will do that so that all can follow the reasonings (at least I hope so). The subject, of course, is not so simple. I hope you will correct me if I say something wrong or imprecise.
Moreover, as you are admirably brief in explaining your points, I will have to interpret, in some degree, what you say at #56, so that I can try to comment on the relevant ideas. Of course, again, if I am misunderstanding your points I apologize, and you are welcome to clarify and correct.
So, I would divide your argument in two related, but different points.
1) The relationship between self-splicing introns and the RNA component of spliceosomal introns.
You say (in response to a previous request of mine):
2) The role of proteins in the spliceosome:
You say:
Now, point 1 is much simpler, while point 2 requires some interpretation, and a more detailed answer.
So, I think that I will proceed this way: I will give first some information about self-spicing introns, so that all can follow the discussion. Then I will address point 1, and finally point 2.
In fact, LECA had not only one complex spliceosome, but two.
– The Origin and Evolution of Eukaryotes. p. 302.
Compound miracles! Is it any wonder Eukarya is considered a distinct domain of life?
gpuccio:
Thanks. I look forward to the additional information when you get a chance.
In particular, I’d be curious as to whether there are experiments showing that the self-splicing introns splice themselves out of an RNA sequence without involvement of any other cellular machinery. Specifically, does the RNA sequence need to be folded correctly before the self-splicing occurs? Or could we just put an RNA sequence in a beaker and the intron would splice itself out?
Arthur Hunt:
Not if one understands the concept. You still have to account for that catalytic RNA and self-splicing introns.
Good luck with that
A book on The Origin and Evolution of Eukaryotes that fails to elucidate the origin and evolution of the spliceosome complexes.
Imagine that gpuccio.
These subsets of snRNAs are nonetheless evolutionarily related to one another and probably originated by gene duplication some time before LECA (Russell et al. 2006).
Eukaryotes invest very heavily in the spliceosome: about 1% of known human and yeast genes encode products deployed in splicing.
– The Origins of Genome Architecture. p. 238
That’s a pretty amazing addition to the genome. And all by “accidental” mutations. Sure. And Santa is going to give you the desires of your heart too. Believe it.
Arthur Hunt (and all interested):
I will start form this statement you made:
“At the heart of the splicesosome sits what is essentially a self-splicing intron.”
It is true that in my OP I have mentioned self-splicing introns, but I have not discussed them. That was essentially for the sake of brevity, and because my focus was on spliceosomal introns.
However, now it’s time to deepen the discussion.
So, I have made my homework, and I will refer in the following discussion essentially to a recent paper
(2015):
“Mobile Bacterial Group II Introns at the Crux of Eukaryotic Evolution”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394904/pdf/nihms673151.pdf
which seems to be a very good summary of what is known about the issue.
The paper is open access, so everyone interested can check the details directly.
I will also draw some information from this paper of 2011:
Group II Introns: Mobile Ribozymes that Invade DNA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140690/pdf/cshperspect-RNA-a003616.pdf
Open access too.
First of all, there are two different types of self-splicing introns: group I and group II.
Again, for the sake of brevity, I will not discuss here group I, because group II is the category which is more directly implied in the possible origin of spliceosomal introns and of the spliceosome, as we will see.
I will start with a very important concept: these are essentially retrotransposons.
Let’s read the very beginning of the first paper:
But where can group II introns be found?
From the second paper:
More in next post.
Are the spliceosomes molecular machines? Michael Lynch seems to think so.
An unexpected layer of complexity in the evolution of the spliceosome was introduced with the discovery that many eukaryotes harbor not just one, but two, such molecular machines (Hall and Padgett 1994; Burge et al. 1998; Patel and Steitz 2003).
– The Origins of Genome Architecture. p. 240
Mung:
Yes, 150-200 proteins involved in the spliceosome, out of about 20000 genes, is about 1%.
A remarkable investment indeed! 🙂
Love your posts gpuccio. Always intriguing (though boring and repetitious).
Thank you and Merry Christmas!
gpuccio:
I, otoh, don’t see the relevance of Type II self-splicing introns to the origin of the spliceosome. I cannot seem to find any connection between the two. 🙂
How might the major and minor spliceosomes have arisen?
– The Origins of Genome Architecture. p. 240
Oh goody! Yes, how? Will Christmas come early this year?
😀
As Eric Anderson wrote @71, I look forward to reading what gpuccio will explain on this fascinating subject.
Thanks.
gpuccio @75:
However, not it’s time to deepen the discussion.
However, now it’s time to deepen the discussion.
gpuccio @75:
As usual, very pedagogical approach to present complex biological information. Thanks.
This thread is very informative.
One thing I did not like about this comment @75 is that it finishes suddenly with this announcement:
“More in next post.”
Now we have to wait for the next episode.
🙂
gpuccio:
Thanks to the spliceosome we know the 20,000 is a base number as there are more than 20,000 proteins. In other words it isn’t “one gene = one protein” scheme, as was once thought. And that scheme was presented because, given blind watchmaker evolution, no one could have ever predicted that cells contained spliceosomes and alternative splicing was the norm. But now that we know all of that of course blind and mindless processes didit.
Mung @74:
It is interesting how preconceptions can cause people to be a sloppy with their language. Quoting:
No change in the “evolution” was introduced. However the spliceosome came about, it came about. Nothing about its history changed with our discovery of additional complexity in the system. 🙂
Furthermore, contrary to what evolutionists typically believe from the assumptions they bring to the table, the discovery of additional challenges to the evolutionary story doesn’t mean the new discovery helps us better understand the evolutionary story. What an objective observer might very well conclude is that the evolutionary story is headed down the wrong path altogether.
What they should have said is:
“The discovery that many eukaryotes harbor not just one, but two, spliceosomes means our made up story about the evolution of the spliceosome isn’t correct. So we’ll have to come up with another made up story.”
There. Fixed it for them.
Arthur Hunt (and all interested):
Now, let’s try to summarize the main points about group II self-splicing introns:
1) They are essentially retrotransposons, mobile elements
2) They can be found in bacteria, rarely in archaea, and in the organelles of eukaryotes (mitochondria and chloroplasts), where they are often degenerate.
3) They are not found in the nuclear genome of eukaryotes.
Now, what is the structure of these special introns?
Look at Fig 1 in the first paper I quoted. You will see the secondary structure of the RNA derived from a group II intron, organized into six domains (DI – DVI).
Now, here it gets complicated. The intron-transcribed RNA is indeed a ribozyme, and has a catalytic activity which can self-splice it from the transcribed mRNA. The catalytic activity is especially implemented by the DV domain, but also other domains contribute.
But the DIV domain is also special, because it includes an ORF, which encodes for a protein, called IEP (intron-encoded protein).
This protein does three different things, by three different domains:
a) A reverse transcriptase domain (RT), which can copy the RNA to DNA for retrotransposition
b) A maturase domain which helps the ribozyme catalytic site to effecting the self-splicing
c) A DNA binding domain and an endonuclease domain which intervene in the final phase of retrotransposition, when the new DNA is inserted in the genome (retro-homing).
Not so simple, is it? 🙂
OK, so to sum up:
– the ribozyme activity in the transcribed intron itself effects the splicing (self-splicing). This process is rather complex, and is mediated by a complex tertiary structure, where the active site is mainly represented by DV.
– however, the splicing probably need, in vivo, the intervention of the IEC, the protein encoded by DIV of the same intron, with its maturase acticity which helps stabilize the splicing by the ribozyme. In that sense, the ribozyme and its encoded protein act as a ribonucleoprotein complex.
– moreover, the IEC, with other domains, can also intervene as a reverse transcriptase and endonuclease to allow retrotransposition and retro-homing of the intron code.
Well, to onlookers: I told you it was not simple.
I apologize again to Arthur Hunt for having to explain these basic points before going on with my reasonings. Any correction or integration will be welcome.
I would leave it at that for today. I will go on tomorrow.
As a final thought, I give you the Uniprot description of the function of a typical IEC, a protein encoded by the DIV of a group II intron.
It is one of the best known, LtrA. In particular, the following relates to the LtrA in Lactococcus lactis, P0A3U0, a 599 AAs long protein. Here is the function section from Uniprot, which illustrates well many of the concepts I have described before:
Moreover, just to have some idea of how conserved is this Ltra protein in bacteria, I have blasted the protein from Lactococcus lactis against a different group of bacteria, Proteobacteria.
I got a best hit of 419 bits, and a range of 372 – 419 bits in the first 100 hits.
That means that the intron-encoded protein shows a good, but not really impressive, conservation in bacteria, at a level of about 0.6 – 0.7 bits per aminoacid (baa), at least in the limited comparison I have done.
I would like all to remember this, because I think it will have some importance in the future discussion about spliceosomal proteins.
OK, that’s all for the moment.
ET:
Yes, of course, but let’s just say that it is about 1% of protein coding genes! 🙂
Mung, ET, Eric Anderson, Dionisio and others:
I am postponing all discussion about the “origin of the spliceosome” and its relations with group II introns, because I believe that we have to have clear and detailed ideas on a number of important things before.
Just have a little patience! As you can see, the subject is rather complex. 🙂
gpuccio:
Lynch agrees:
No group II intron has been found in a eukaryotic nuclear gene. (p. 244)
Ir’s amazing, all those mitochondrial genes that moved into the nuclear DNA, but none with a group II intron. What are the odds.
gpuccio:
ok. Guess I’ll have to break out my copy of Intervening Sequences in Evolution and Development. Chapter 6 is “Different Types of Introns and Splicing Mechanisms.”
🙂
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.
You are very kind. Personally, I call such a person a jackass. But that’s just me.
Thanks Gpuccio on another engaging post. I look forward to Arthur Hunt’s input regarding #50 #51 #56 assertions as well.
As we track through this discussion, I wonder how many assumptions come from the heart of the matter, that are made for blind, unguided evolution to progress to the Spliceosome?
Will we get detailed step by step evolutionary progress of interdependent systems coordination and organization?
Driven by unguided, gradual step by step “process” or the usual narrative that “could have” or “may have likely” happened?
I’m intrigued that this may offer up something unique in both sides of the discussion.
It is now clear that introns are not all alike, even in the most general terms.
– Intervening Sequences in Evolution and Development. p. 112
gpuccio,
If you let me know which kind of introns and/or which aspects of the spliceosomes you are studying deeper I’ll see what I can contribute.
So far you appear to be spot on. Good work.
Cheers
#44 PAV, thanks for book link.
DATCG:
My experience is that you’ll find far more discussion of how the different sorts of introns evolved with far less devoted to to the origin and evolution of the spliceosomes.
They will cover one and pretend to have thus addressed the other.
Found link, is this the correct Arthur Hunt?
Arthur Hunt – UKY Research Gate Profile
#95 Mung, yes, it’s my expectation as well.
Arthur Hunt (and all interested):
So, let’s take again the discussion.
I think we have enough data now to answer point 1.
Your point was:
“There is indeed an abundance of evidence for the proposition that the structural and catalytic components of the spliceosome and group 2 introns are basically the same.”
and, (which is more or less the same):
“At the heart of the splicesosome sits what is essentially a self-splicing intron.”
Is that true?
In the light of what we know, I would definitely say: yes!. With some reservations that I will clarify.
In my comment #54 I had already stated that I had nothing against this concept, I just needed more information. After some research, I can say that the concept is correct.
Let’s see some details:
a) We have seen that the ribozyme catalytic activity in the group II intron RNA is mainly localized in one domain, DV. Well DV is also the only domain whcih is highly conserved, and at the same time the only domain which has high homology with one of the spliceosomal RNAs U6. On the other hand, U6 is also the most sequence conserved spliceosomal RNA, and directly involved in the catalysis. So, we can certainly say that this important piece of the complex is shared between the group II ribozyme and the spliceosomal catalytic site, both at sequence and at structure level.
b) The rest of the RNA component is rather different in the two context, at sequence level. But we can accept that there is a very strong structure similarity, and that essentially the catalysis works in a very similar way in group II introns and in the spliceosome.
I must say that the more i read about group II self-splicing introns, the more I become convinced that they are a fascinating structure, and that they could make a very good argument for ID, in their own right. 🙂
However, let’s not digress!
For those who are interested in the basic structural features of the catalytic site, I would recommend this very good, although very technical, video:
https://www.youtube.com/watch?v=ESXo3fTThBI
Now, a few more points:
c) Although the structural working of the catalytic site is highly comparable, it is however realized in very different ways in the two contexts.
In group II intron RNA, indeed, almost everything depends on the six domains in the one molecule, which fold into a very complex 3D structure. For example, the main role of scaffold here is implemented by DI, the biggest domain. Moreover, the only protein contribution is provided by the IEP, with its maturase activity.
On the contrary, in the spliceosome we have five different RNA molecules, only one of which really corresponds to one domain in the group II intron RNA, and each of these five snRNAs is part of a complex with its specific proteins, a lot of them. The global interaction of all these ribonucleoproteins in some way reconstructs the structure of the catalytic site.
Even if we consider only the final shared catalytic activity, I would definitely say that the two contexts are very different, and that going from the first to the second is no simple matter, and requires a lot of engineering.
More in next post.
And of course, given an hypothesis of intelligent design, one might expect to find such re-use.
Mung:
Yes, of course!
Great article. Thanks for taking the time to put this together.
As a broad-brush analysis that is intuitive for most let me offer the following.
Suppose we put together an analogy between the complexity of the spliceosome and the English text necessary to describe it in detail. In this back of the envelope exercise I have made every effort to be charitable to Neo Darwinism–extraordinarily charitable.
In Stephen Meyer’s book, “Darwin’s Doubt” he quotes Michael Denton as saying that the ratio of meaningful English sentences or phrases of 100 characters to character phrases that are unintelligible is 1 / 10^100.
The article here references the paper: “Spliceosome Structure and Function”, stripped of the TOC and Bibliography, this paper is about 65,000 characters. There are many pictures. It has been said that a picture is worth a thousand words. I think that is an understatement in this case. But let us say there are 10 pictures and assign 1000 words to each; each word has 4-5 letters. So roughly, let’s say there are 100,000 English letters needed to describe the spliceosome based on this one article. A very low estimate for the adequacy of human informational conveyance especially considering we don’t know everything there is to know about how the spliceosome works. But let’s go with that anyway. Let’s further assume that 100 characters is about the minimum distinct informational quantity that can be meaningful. Let’s say that we have as many monkeys typing new English text phrases as we have grains of sand on earth (10^19) and that each monkey was turning out a new 100 character string each second. There have been about 10^18 seconds since our planet was born. So there could be only about 10^37 total 100-character English sentences/phrases generated since the birth of our planet using these assumptions. And let’s further assume that every valid (meaningful) 100 character English phrase generated by our monkeys just happened to be suitable as a new (i.e. non-redundant) useful explanation for a spliceosome–in other words, let’s factor out natural selection completely. These are all preposterous assumptions of course and all wildly favorable to Neo-Darwinism.
Even with these assumptions the probability of obtaining a text to describe the splicesome would fall short by about 66 orders of magnitude. 10^103 – 10^37
Conclusion: Neo-Darwinism is a canard. But it is only the second greatest intellectual canard in human history. The greatest intellectual canard in human history is the metaphysical doctrine of materialism. It is the assumption of the truth of materialism that necessitates Neo-Darwinism and it is the believed truth of Neo-Darwinism that forms the necessary condition to support materialism. Together they form a grand intellectual tandem canard–a magnificent intellectual catch-22 and a supreme example of human gullibility.
Be well all. Have a great holiday.
gpucci: “… they could make a very good argument for ID, in their own right.” Probably correct. I can’t judge the IC in complex molecular machines but I think there’s two logical points that are relevant here. The contention that a structure is IC is not a concession that a smaller structure within it is not IC. And — even if the smaller structure is not IC, it doesn’t affect the IC of the larger structure.
Perhaps a bit OT for this thread, but interesting nonetheless?
Looking for any coverage of the origin and evolution of the spliceosomes in The Evolution of the Genome Edited by T. Ryan Gregory. I didn’t find any. Amazing.
But I did find a pie chart on p. 553 that showed the “distribution of the homologs of the predicted human proteins.” [ETA: This has nothing to do with spliceosomes. Different topic.]
1% had no animal homology.
Vertebrate only 22%
Vertebrates and other animals 24%
Animals and other eukaryotes 32%
Eukaryote and prokaryote 21%
Prokaryotes only < 1%
Is this really the pattern we would expect to see given common ancestry?
gpuccio @98:
“Although the structural working of the catalytic site is highly comparable, it is however realized in very different ways in the two contexts.”
This seems like a very important point.
Isn’t it?
@98:
This is very important to consider seriously.
What’s the official explanation for transitioning from one context to another?
Arthur Hunt (and all interested):
Now, another important point I would like to discuss.
Group II introns are supposed to be at the origin of spliceosomal introns. But also of the retrotransposon component of metazoa genome. IOWs, of most of our genome: introns and a great part of intergenic non coding DNA. That’s an important theory, and I want to discuss it in some detail.
Moreover, group II introns have been in some way involved in a theory about the evolution of spliceosomal proteins. I will discuss that point later, when I come to point 2 (the proteins).
Let’s refer again to the Lambowitz and Belfort paper, the first I quoted.
In brief, group II introns are obviously similar to other retrotransposons, in particular non-LTR retrotransposons (SINEs and LINEs). You can find some details in the paper section:
“Mobile group II intron-eukaryotic retrotransposon relationships”
However, the possible derivations of SINEs and LINEs (important intergenic forms of non coding DNA) from bacterial group II introns, while fascinating, are not really relevant for our discussion here, so I will not go into further detail about this aspect.
Much more interesting, for us, is the idea that eukaryotic spliceosomal introns, those which are spliced by our friend the spliceosome, may derive from group II self-splicing introns.
The theory goes more or less this way: group II introns were carried on from prokaryotes in the endosymbiont events, and then “invaded” the eukaryotic genome, becoming the spliceosomal introns.
That is possible, but there is one major problem: group II introns cannot be found in the eukaryotic nuclear genome (only in the organelles), and spliceosomal introns are rather different.
For example, the conserved splicing signals in 5′ and 3′ are similar, but not the same:
GUGYC and AY in group II introns
GU and AG in spliceosomal introns
and, of course, spliceosomal introns, as far as I know, lack any ribozyme activity and do not encode IEPs.
The two references given by the paper for this theory are indeed very old (1991, Cavalier-Smith and Palmer), and I could not find more recent support to the theory.
I am not really convinced, I must say. However, even if spliceosomal introns “evolved” from group II introns, here again some major process of reorganization obviously took place: the fact remains that group II introns are absent from eukaryotic nuclear DNA, that spliceosomal introns cannot self-splice and require the spliceosome, and that obviously genes cannot be successfully transcribed and translated unless introns are spliced from mRNA.
OK, more in next post, when possible! With the discussion about proteins, at last! 🙂
In the meantime, my best wishes for Christmas time to all! 🙂
nkendall:
Thank you for your very interesting intervention: I love the analogies between biologic information and human language! 🙂
You could perhaps be interested in this older OP of mine:
An attempt at computing dFSCI for English language
https://uncommondescent.com/intelligent-design/an-attempt-at-computing-dfsci-for-english-language/
Have a great holiday! 🙂
hnorman5:
I absolutely agree. Thank you for pointing to that. 🙂
Dionisio:
“What’s the official explanation for transitioning from one context to another?”
I don’t think they have one.
Certainly, not one that tells us “exactly” how that happened!
Probably, not even vaguely! 🙂
Have a very beautiful Christmas! 🙂
Mung:
Very interesting numbers, indeed. They correspond very well to my data about the vertebrate transition.
A wonderful Christmas to you, too! 🙂
Let me ask a question about group II introns. If you don’t know the answer I can look it up myself, you don’t have to do that for me. 🙂
Spliceosomal introns occur within protein coding regions as described in the OP. Is that also true of group II self-splicing introns?
Another way to ask the question is that spliceosomal introns permit alternative splicing. Is the same true of group II self-splicing introns?
Another thing I’d like to point out is that it would be quite miraculous that if self-splicing introns existed in the nuclear genome that they no longer do so. They were either all magically converted to something else or miraculously removed. All of them.
Ain’t evolution grand.
gpuccio @106:
“Group II introns are supposed to be at the origin of spliceosomal introns. But also of the retrotransposon component of metazoa genome. IOWs, of most of our genome: introns and a great part of intergenic non coding DNA. That’s an important theory, and I want to discuss it in some detail.”
I look forward to reading more about this here.
Thanks.
gpuccio @109:
I thank God for allowing me to read your serious scientific articles and comments.
I thank you for all the time an effort you dedicate to your highly documented articles and for being so concerned about explaining difficult topics in very easy to understand terms and style.
May you along with your family and friends have a blessed Christmas.
gpuccio @106:
“…there is one major problem: group II introns cannot be found in the eukaryotic nuclear genome (only in the organelles), and spliceosomal introns are rather different.”
“…the fact remains that group II introns are absent from eukaryotic nuclear DNA, that spliceosomal introns cannot self-splice and require the spliceosome, and that obviously genes cannot be successfully transcribed and translated unless introns are spliced from mRNA.”
I would like to read more on this.
The spliceosome
The spliceosome: the most complex macromolecular machine in the cell?
A day in the life of the spliceosome
The recent origins of spliceosomal introns revisited
And yes:
The Spliceosome: Design Principles of a Dynamic RNP Machine
gpuccio @106:
Well said. Thanks for taking time to lay this out in detail. This is very valuable.
—–
And if you’ll permit me to tease for a moment, even those “self-splicing” introns aren’t really self-splicing (in the sense of being fully autonomous), are they? 🙂
Eric Anderson:
“And if you’ll permit me to tease for a moment, even those “self-splicing” introns aren’t really self-splicing (in the sense of being fully autonomous), are they?”
To be precise, it seems that self-splicing can occur autonomously only in vitro, and under non physiological conditions.
In vivo, other factors are needed, probably at least the intervention of the IEC protein, with its maturase activity.
To all:
I have found another interesting and recent paper about the “evolution” of group II introns, of spliceosomal introns and of the spliceosome.
Evolution of group II introns
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424553/pdf/13100_2015_Article_37.pdf
From the abstract:
Here is the “explanation” for the transition from group II introns to spliceosomal introns and to the spliceosome:
Emphasis mine.
I will not comment that for the moment. I have added emphasis to the points that are more interesting, or simply more incredible. Please, read and judge yourselves.
I must say however that, although IMO this is as far from an “explanation” as one can imagine, and so much near to the classical darwinian concept of a “just so story”, still it is a good and useful summary of the issue we are discussing.
One last clarification: I have not yet addressed the important point of the relationships between group II introns and the spliceosome protein Prp8. This is an important point, but I will discuss it in detail in the context of the role of spliceosomal proteins.
Mung:
“Spliceosomal introns occur within protein coding regions as described in the OP. Is that also true of group II self-splicing introns?”
This is not an easy answer. Group II introns are localized essentially in two different sites:
1) Bacterial genome
2) Organelles in lower eukaryotes and plants
Not much is known about these interesting entities.
In the bacterial genome, it seems that they are mainly localized in less important and less conserved genes, and sometimes in intergenic regions. Remember, introns are however rather rare in prokaryotes.
In organelles, they are more often linked to housekeeping genes, but they are often more or less degenerate, and often they do not have ORFs.
“Another way to ask the question is that spliceosomal introns permit alternative splicing. Is the same true of group II self-splicing introns?”
Alternative splicing is essentially an eukaryotic function. In prokaryotes, transcription and translation are strictly coupled, and alternative splicing does not occur, as a rule.
I think I may have read something about minimal alternative splicing in prokaryotes, but I am not sure, and I cannot find the reference. However, even if something like that exists, it’s rather the exception.
“Another thing I’d like to point out is that it would be quite miraculous that if self-splicing introns existed in the nuclear genome that they no longer do so. They were either all magically converted to something else or miraculously removed. All of them.
Ain’t evolution grand.”
Please, look at my post #118 for some just so story about that point! 🙂
Evolution as problem solving. I love it.
gpuccio @117:
Thanks for indulging me (I know it isn’t the key point you are focusing on).
“. . . it seems that self-splicing can occur autonomously only in vitro, and under non physiological conditions.”
Meaning, not in the real world?
Hmmmm . . .
I’m not quite ready to pronounce any conclusions yet, but this is starting to sound suspiciously like those self-replicating molecules we keep hearing about that are supposed to kick off the whole abiogenesis creation story (but which don’t exist).
I’ll have to keep my eye on these so-called self-splicing introns a bit more . . .
Eric, Merry Christmas.
Whether in vivo or in vitro, both are in the real world. A self-replicating molecule in vitro would still be a major design accomplishment.
Let’s not hang our Santa hats on that. 🙂
Mung:
One wonders how this “self-splicing” takes place in vitro. Do they add reagents, or proteins? What’s involved?
IOW, are we dealing with a “directed” process in vivo, which scientists stumble upon in vitro?
PaV:
Not me. I believe it takes place in vivo.
I can understand why gpuccio was trying to avoid going through all the different sorts of introns and the evidence for them and for the mechanisms associated with their splicing. 🙂
I’m not going to be the one to ask him to start over from scratch, lol!
Mung:
My point was that in vitro requires an ‘intelligent agent’ to do what is done quite naturally in vivo: that is, a “directed” process—one that has a “direction” given to it by some intelligent agent.
Mung @124:
“Whether in vivo or in vitro, both are in the real world.”
Fair enough. You know what I mean. Maybe we could say “natural world” instead.
“Not me. I believe it takes place in vivo.”
On what basis? Just because they call it self-splicing doesn’t make it so.
I can certainly believe that if an mRNA strand has the right sequence, is carefully shepherded to the right location, protected from interfering cross reactions, and three-dimensionally positioned such that the splicing can take place, then the relevant molecule could trigger a splicing event.
Sure, I can buy that. And we could even call it “self” splicing if we wanted to. The risk is that people tend to see these “self” driving processes as though it is all just chemistry doing what it does all by itself — move along folks, nothing to see here. This is incredibly naive and is anathema to our (growing) understanding of what is actually required to engineer an organism.
So, no, I don’t feel bound by the terminology and the labels biologists put on things. I prefer to press and see if the label actually fits. For example, just because Joyce calls his molecules “self-replicating” doesn’t make them so. And I’m starting to suspect that just because people call certain mRNA elements “self-splicing” might not make them so. In contrast to the former, I haven’t looked into the latter in a lot of detail, so I’m open to being corrected. But so far, my suspicions appear to be on the right track.
Agreed. I’m still patiently waiting . . . 🙂
I don’t. But I also don’t feel any compunction to give away the store or cede ground were it need not be ceded. Particularly (in the case of self-replicating molecules) when the whole materialistic creation story is absolutely dependent on the existence of these never-before-seen, no-reason-to-believe-exist, highly-unlikely entities.
Again, apologies for the side track. gpuccio is bringing up some incredibly important points, with which I am in agreement. This “self” issue just jumped out at me as another interesting issue that we shouldn’t be too quick to ignore.
To all:
I am sorry that my short answer to Eric is causing some confusion. I will try to clarify better.
When we say that group II introns are self-splicing, we mean that it’s the intron RNA itself that catalyzes its splicing from the pre-mRNA. IOWs, the catalytic site and activity are formed by the intron RNA itself, and catalyze their own splicing from the mRNA. If you think that this is an amazing result of clever engineering, I fully agree with you! 🙂
However, this capacity at self-splicing is obviously connected to the retrotransposon nature of these entities, and to their ability to move and retro-home.
When we say that group II introns can autonomously self-splice in vitro, we mean that they can do so, to some extent, out of a cellular environment. IOWs, you take the pre-mRNA with the group II intron, you put it in a tube, and it can self-splice. Of course, you always have to provide some basic conditions, pH, ions, temperature, and so on, for the reaction to happen, but no major cellular components, like other proteins, are necessary. Mg2+-ions are always necessary for the intron RNA to fold into the correct tertiary structure and for its catalytic function
When we say that self-splicing can happen in vitro, but in non physiological conditions, it means that strangely the reaction autonomously happens only in conditions that would not be likely in a living cell, in particular high concentrations of a salt with a monovalent cation. A somewhat high temperature is also necessary (45°).
In vivo, the reaction needs the help of other components, in particular proteins. While I suppose that other proteins can be involved, the main role seems to belong to the intron IEP protein, IOWs, the protein coded by the intron itself by the ORF located in the DIV domain (remember that transcription and translation are strictly coupled in bacteria, while in eukaryotes that are separated by the nuclear membrane). The specific activity of the IEP protein which stabilizes the intron ribozyme is usually called maturase activity.
I hope this clarifies some of the issues that have emerged in the discussion. However, if you are interested, and really want to suffer ( 🙂 ), here you can find a lot of details:
Group II Introns: Structure and Catalytic Versatility of Large Natural Ribozymes
https://www.researchgate.net/publication/10653386_Group_II_Introns_Structure_and_Catalytic_Versatility_of_Large_Natural_Ribozymes
I quote a simple passage which summarizes well what I have said here:
Mung:
“I can understand why gpuccio was trying to avoid going through all the different sorts of introns and the evidence for them and for the mechanisms associated with their splicing.”
You bet! 🙂
Arthur Hunt (and all interested):
And now, the spliceosome proteins.
Arthur Hunt, having set some basic points with all those who are following the discussion, and having essentially accepted you point 1, I am going now to address you more directly to discuss point 2.
Let’s see it again. You said (#56):
Now, that is maybe a little cryptic, so I will interpret it a little bit, and of course you are free to clarify if I am misunderstanding your point.
It seems that you are saying:
“The role of proteins in the spliceosome is somewhat aspecific, and therefore not so relevant from the informational point of view. Evidence of that can be found in the fact that proteins help the splicing in prokaryotes, and that those proteins are completely different from those of the spliceosome.”
OK, so I will comment the point in that form, unless you intervene to clarify better.
But I will try to widen a bit the discussion on this issue, because it is a very important one. So, I will follow more or less the following line of discussion:
a) I will try to explain why in my OP I have focused my attention on the spliceosome proteins, and not on the RNA catalytic core.
b) I will discuss the roles of the proteins in the spliceosome.
c) I will discuss the issue of the differences between prokaryotic proteins involved in splicing, and the spliceosome proteins, and what those differences may imply.
d) Finally, even if that point was not raised by you, I will debate in some detail the presumed derivation of Prp8, my favourite spliceosomal proteins, from gourp II self-splicing introns.
That will take some time, I imagine, but at least I have traced a general blueprint of what I want to say. That will probably be of help to me and, I hope, to those who will read my next comments.
A very Merry Christmas to all. I thought I would leave gpuccio and everyone following this a small gift, an additional pointer to another interesting aspect of this discussion. It is in the form of a few words for Google: try searching for information about the maturation of the Chlamydomonas chloroplast psaA mRNA.
Enjoy!
gpuccio @127:
“…take the pre-mRNA with the group II intron, you put it in a tube, and it can self-splice.”
That’s really cool!
Definitely the discussion between gpuccio and the distinguished professor Arthur Hunt has turned very insightful, despite its strange start @25.
Has distinguished professor Arthur Hunt anything to say on what gpuccio has explained so far?
Does he agree with everything gpuccio has stated so far?
Just curious.
gpuccio @127:
Quite interesting, isn’t it?
the maturation of the Chlamydomonas chloroplast psaA mRNA- just something else blind and mindless processes cannot account for…
First of all … Merry Christmas to all.
Now my comment:
I won’t pretend to be able to fully follow this quite technical post and all the follow up comments — very fascinating.
The very title “a molecular machine that defies any non-design explanation.” shouts a challenge of “evidence … evidence … evidence”
So here is yet another — of many — instances of evidence for Design, for Intelligent Design given here at UD. Its this sort of evidence that several (looking at you rvb8) contributors here claim is totally lacking in the ID argument.
Perhaps rvb8 is out for coffee, or otherwise unavailable, but after 100+ comments on this post not a single one from rvb8 refuting this as a piece of valid evidence.
Hopefully rvb8 is indeed out for coffee and deep in study of what is presented here. Hopefully after being forced into a corner of objectivity and following evidence such as presented here … to a logical, not ideological conclusion, he might at long last sense a sort of light coming on.
One can only hope!
Arthur Hunt (and all interested):
Merry Christmas to you and thank you for your participation here.
Your “Christmas gift” is very interesting, and helps me understand better some aspects of your previous statements. I will consider it in the following discussion, of course.
For all who may be curious, it is about some specific and very intriguing aspect of splicing in plant organelles, chloroplasts.
Shapiro – Senapathy Algorithm
This would be the author of:
Independent Birth of Organisms. A New Theory that Distinct Organisms Arose Independently from the Primordial Pond, Showing that Evolutionary Theories are Fundamentally Incorrect
Arthur Hunt (and all interested):
So, I will go on with my declared schedule, and include at the appropriate step the new information kindly provided by Arthur Hunt at #130, and which can be important to understand his point of view (I must say that our friend from the other side is using a remarkable, although sometimes a little frustrating, “Ars Maieutica” to clarify his thoughts! 🙂 )
So, let’s go to the first point, which is not so difficult:
a) I will try to explain why in my OP I have focused my attention on the spliceosome proteins, and not on the RNA catalytic core.
One easy answer would be that I have much more familiarity with proteins than with nucleotides. That’s absolutely true. But it is not the main reason.
The main reason is informational.
I have specified in my OP the individual lengths if the five snRNAs which are the catalytic part of the spliceosome.
I have also added about them:
“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.”
We have also seen in the discussion that those points are valid also for group II introns, even if type II intron RNAs can be much longer, especially when they include the ORF for the IEP in their DIV domain.
OK, let’s consider this from a quantitaive informational point of view, IOWs from an ID point of view.
If we sum the length of all five spliceosomal snRBAs (in humans), we get:
719 nucleotides
So, the total maximum information content that can be expressed by those 5 genes, taken together, is:
4^719 = 1438 bits
But, of course, this is not the true functional information of the sequences. We know that, with the exception of U6, the sequences are scarcely conserved, while the structures are very conserved. That means that the sequence-structure relationship is very flexible.
I have no idea of how big the true functional information maybe, that would require detailed studies of the sequence conservation of these genes. Let’s say that it is certainly rather lower that the total possible information content. Let’s imagine that it can be in the range of a few hundred bits, just for the sake of discussion. That’s not unlikely, the U6 gene alone is very conserved, and it could contribute 100 – 200 bits of functional information.
The point is: that functional information is a big amount from a general point of view, certainly beyond the capacities of RV + NS (see my previous posts on those points). But it is “relatively” small if compared to the huge amount of functional information we can observe in some proteins, and in particular in the proteins that are part of the spliceosome.
We have seen in the OP that Prp8, alone, exhibits at least 3345 bits of human-conserved information in single celled eukaryotes (4211 in fungi). If you consider that we are dealing with exponential values, that’s a lot more!
Beware, I am not saying that the RNA catalytic site of the spliceosome (or of group II introns) is not complex: as I have said, it is an extraordinary accomplishment of engineering, from a biochemical point of view. And yet, moderate amounts of functional information are sufficient to encode it (if we can call “moderate” a few hundred bits of information).
ID has a quantitative approach to functional information: therefore, with all respect for the RNA component, the protein component seems more “interesting” from an ID point of view.
Another aspect has also been detailed in the discussion stimulated by Arthur Hunt: the basic information for the catalytic site was already present in bacteria, in group II introns. So, the spliceosome is reusing that information, even if, as we have discussed, a major re-engineering is obviously necessary to go from the single RNA molecule ribozyme in group II introns to the fragmented RNA + multiple proteins structure of the catalytic site in the spliceosome. But the information for such a re-engineering is not easy to quantify exactly.
On the other hand, many of the proteins in the spliceosome are informational novelties, as we have seen, with complex and conserved sequences that practically appear for the first time in the eukaryotic spliceosome. That too makes them extremely interesting for an informational analysis from an ID point of view.
I understand that Arthur Hunt is probably biased towards RNA, and tends to somewhat under-emphasize proteins. That can be expected, given his specific background. I will come back to that point in the course of the discussion. However, most of the evidence that I have presented in my OP is about proteins, and most of the methodology I have developed deals with proteins, so I will stick to proteins in the rest of the debate.
Point b) in next post.
ayearningforpublius @135:
I see your valid point, but note that gpuccio is very serious in his scientific articles and follow-up commentaries, hence his discussion threads don’t need trolls.
In this current thread we see a distinguished professor at a university in the US presenting scientific arguments that have had the positive effect of making gpuccio write more on this interesting topic. Interestingly, so far his highly educated interlocutor hasn’t commented back on gpuccio’s scientific arguments.
At the end the readers benefit from their exchange.
This thread has had almost ten times more non-commenting visitors than commenting ones in its first four days. That’s not too bad.
Merry Christmas GP, Merry Christmas Mung, Merry Christmas all…
gpuccio @138:
That’s it! I couldn’t figure out what was going on, but it definitely looks like a convoluted version of the Socratic method:
https://en.wikipedia.org/wiki/Socratic_method
Thanks for clarifying this.
UB:
Merry Christmas to you, my friend! 🙂
gpuccio @138:
“…many of the proteins in the spliceosome are informational novelties, as we have seen, with complex and conserved sequences that practically appear for the first time in the eukaryotic spliceosome.”
Would the distinguished professor that posted @25 ever realize that he’s on the losing side of this debate?
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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
(*) error admitted
(to be continued…)
Arthur Hunt (and all interested):
Now, let’s talk of the proteins. My arguments are already clearly expressed in the OP, so I will try not to repeat them too much.
Let’s see again Arthur Hunt’s statement:
My further interpretation:
“The role of proteins in the spliceosome is somewhat aspecific, and therefore not so relevant from the informational point of view. Evidence of that can be found in the fact that proteins help the splicing in prokaryotes, and that those proteins are completely different from those of the spliceosome.”
I think that interpretation remains correct. However, when I wrote that I was thinking that Arthur Hunt was referring mainly to the IEPs, IOWs the proteins encoded by group II introns themselves, by the ORF in DIV, essentially in their rather rare occurrences in bacterial genomes, of which LtrA in Lactococcus lactis is one of the best known examples (see my post #86).
Instead, according to his suggestion in #130, it seems that he is more interested in the “maturation of the Chlamydomonas chloroplast psaA mRNA”. That was not easy to catch, because that is a very specific issue (and I am greatful to Arthur Hunt for pointing at it), and it is not exactly a prokaryotic system, but rather a system in an eukaryotic single celled organism, involving the chloroplast (which is probably of prokaryotic derivation).
That complicates a little our discussion, because the two scenarios (IEP proteins like LtrA helping the self splicing of group II introns in bacteria and proteins helping in trans splicing of a specific gene in unicellular algae) are quite different. So I will have to deal with them separately.
One warning to all who are following this discussion. It is not simple, and it will become even less simple. I will try to be as clear as possible, but if anyone has doubts or questions, please be free to ask or comment.
As a first, easy step, I will briefly summarize my main argument from the OP:
a) The spliceosome is a wonderful, and very complex, molecular machine. As clarified earlier, we are now debating specifically the functional complexity linked to the protein part, having already discussed in some detail the RNA catalytic core.
b) The spliceosome is a rather universal complex in eukaryotes. Rare apparent exceptions are interpreted as cases of loss of information. The universality of the spliceosome is a direct consequence of the universality of spliceosomal introns in eukaryotes. No eukaryotic transcription and translation could work without the spliceosome, which is the only tool which can excise spliceosomal introns.
c) The spliceosome is essentially eukaryotic: the proteins which make it are, in most cases, a complete eukaryotic novelty. I have given examples of that, but we will discuss that aspect again for Prp8 in this discussion.
d) Spliceosome proteins are, in most cases, exceptionally conserved in all eukaryotes, from single celled organisms to humans. That point is well demonstrated by measuring the human-conserved information in different single celled eukaryotes, as I have done in Fig. 4. Prp8, again, is probably the most conserved protein in the spliceosome, and its level of conservation (1.8 baa from fungi to humans) rivals with the most conserved proteins in eukaryotes.
e) A final important point is that the spliceosome certainly has an important role in alternative splicing, a regulation network whose functional importance in eukaryotes is recognized practically by all.
I will dedicate some time to this last point.
The ability of the spliceosome to take part in transcription regulation through alternative splicing, and probably other mechanisms, seem to be strictly related to its dynamic nature as a malleable molecular system. I quote from:
“The Spliceosome: The Ultimate RNA Chaperone and Sculptor”
http://www.cell.com/trends/bio.....15)00211-X (paywall)
More in next post.
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
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
(to be continued…)
Serious error found @146:
(and I am greatful to Arthur Hunt fro pointing at it),
(and I am grateful to Arthur Hunt for pointing at it),
The word ‘grateful’ got affected by a deleterious RV where the letter ‘e’ got misplaced
“fro” instead of “for” ? oops!
the letters o and r were swapped!
🙂
@146 achtung!
“One warning to all who are following this discussion. It is not simple, and it will become even less simple. I will try to be as clear as possible, but if anyone has doubts or questions, please be free to ask or comment.”
Ok. Thanks.
Dionisio:
If only I could RV (possibly helped by NS made by you) compile my answers to Arthur Hunt!
That would be a lot of work spared! 🙂
@146, another ‘major’ error:
letters ‘k’ and ‘a’ swapped places within the word eukaryotic
‘ak’ instead of ‘ka’
euakryotic eukaryotic
Yes, I see what you mean @150
Well, what can I say?
C’est la vie, mon ami
🙂
To poorly educated folks like me, Kentucky was associated with things like https://www.kfc.com/
and to my neighbors also https://www.kentuckyderby.com/
But now I may associate it with… ok, let’s not talk about that here. 🙂
@146
Non deleterious RV detected:
The letter ‘u’ was accidentally repeated: buuut
A semantically-endowed word processor installed in my Surface tablet detects and highlights most ‘typos’ and suggests replacements.
Dionisio:
OK, my Natural Selector. Done. 🙂
*poof!* is not an explanation?
Mung,
Yes, these days that would count as a valid explanation, because anything -except ID- counts.
🙂
ant? and
Prp8, again, is probably the most conserved protein in the spliceosome, ant its level of conservation (1.8 baa from fungi to humans) rivals with the most conserved proteins in eukaryotes.
After all that gpuccio has explained so well, it seems like professor Arthur Hunt owes us some explanations too.
Here’s a thread I posted just over a month ago: Evolution as a Ralph’s Supermarket.
It’s always the same thing: in the minds of Darwinian thinkers, the presence of proteins, or of other constituent parts, is necessary and sufficient to explain any complex structure found in living cells.
My comment@27:
If the objection is made, “Well, the prokaryotes came first, and they had a catalytic splicing capacity, and the “origin” of this catalytic activity is part of the OOL,” then my response would be: “First solve this problem of overcoming this huge number of permutations, and, then you can start worry about OOL–which is a much more difficult problem, one which includes this catalytic spliceosome cunundrum.”
What I’m saying is this: no matter what gpuccio writes indicating the immense complexity, Arthur Hunt will content himself by saying, “Well, yes, it’s complex, but we find these structures there. They had to come from somewhere. It’s just a matter of time–you know given all the replications that can take place.”
It’s pointless to point out the obvious to those who discount the obvious.
PaV:
I had not seen that you had already discussed the spliceosome! Good! 🙂
Matzke and Pallen adhere to the “Ralph’s Supermarket” concept of evolution for bacterial flagella:
From The Origin of Species to the origin of bacterial flagella, via Ralph’s Supermarket
Arthur Hunt (and all interested):
I would like to address now the theory, cited by many papers, that group II self-splicing introns would be the origin not only of spliceosomal introns, but also of the spliceosome (and, but that is not so interestoing for us here, of a lot of intergenic non coding DNA, like LINEs and SINEs, and maybe telomerases).
So, what is the relationship between group II introns and the spliceosome?
There are two aspects.
The first has been already discussed here in detail: the RNA catalytic core of the spliceosome (the five snRNSa) is clearly derived from group introns. That cannot be denied. However, I have tried to emphasize that the derivation is not at all simple, because only the strict catalytic site (DV – U6) is really conserved, while the rest is different, fragmented and recostructed in the spliceosome through the contribution of the many spliceosomal proteins that form the RNA-protein complexes or snRNPs.
OK, I will not come back to this.
The second point, instead, still need to be discussed. Group II introns are also belieeved to be in some way the “ancestors” of spliceosomal proteins.
Is that true?
Essentially not, but we need to understand why such a claim is made, and what it really means.
Some important points:
1) The claim is made, really, only for Prp8. IOWs, simplifying, Prp8 would be derived from group II IEP, the proteins encoded by the ORF in DIV. Or from some similar retro-transcriptase protein in prokaryotes.
2) How is that possible? In my OP, I have clearly stated that Prp8, like other spliceosomal proteins, maybe more than any other, is an eukaryotic protein, that it shows no homology with any eukaryotic protein.
Am I wrong?
No, I am not. Blasting Prp8 vs prokaryotes, we get no hits (except, as said in the OP, for 3 false hits which are clear errors in the database).
But there is more.
If you look at the already quoted paper:
Mobile Bacterial Group II Introns at the Crux of Eukaryotic Evolution
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394904/pdf/nihms673151.pdf
and look at Fig. 6:
Comparison of Prp8 to group II intron and related RTs
you can see that Prp8 is compared to 5 different molecules, with which it is supposed to have structural similarities.
The first is group II IEP (maturase) LtrA from Lactococcus lactis, of which I have already spoken at #86. Number 2 and 3 are two maturases from plants. the last two are other proteins with RT activity.
OK before we consider why these proteins are supposed to be possible “ancestors” of Prp8, let’s clarify without any doubt one thing:
I have blasted exactly the molecules referred in the Figure: yeast Prp8 against the other 5, and the result is: absolutely no hit.
Indeed, if you are curious, the bitscores and E values are, in order:
20.0 7.6
23.1 0.9
21.6 2.6
20.8 4.8
26.6 0.099
No significant homology at all, with any of the 5 possible “ancestors”.
Now, I would like to remember her, for comparison, that Ltra, the protein which sghould be the best candidate as an “ancestor” of Prp8, is rather well conserved in bacteria, as I have shown in my post #86: about 400 bits of conserved sequence information.
But then, why do they say that those proteins are somewhat related?
The answer can be found in the following papers:
Prp8, the pivotal protein of the spliceosomal catalytic center, evolved from a retroelement-encoded reverse transcriptase
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078730/pdf/799.pdf
and
Crystal structure of Prp8 reveals active site cavity of the spliceosome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672837/pdf/emss-50962.pdf
This papers, correctly, show some reasons to believe that some evolutionary connection could exist between Prp8 and those proteins. But what are those reasons?
a) Enhanced homology queries have shown the presence of some putative domains in Prp8 which show significant (but low) homology with existing domains. You can find them in Fig. 1 of the first paper. Of those domains, the one that is relevant for the derivation from RT molecules is the RT domain (AAs 950 – 1220 in yeast Prp8). This domains shows, with those enhanced sequence analyses, some homology to other existing RT proteins, both bacterial and eukaryotic. That is confirmed by the second level of data:
b) Structural data show some structural similarity between the RT putative domain in Prp8 and RT domains in the other RT proteins. Finally:
c) The second paper shows that the RT and En putative domains of Prp8 form a cavity that helps accommodate the RNS catalytic structure of the spliceosome. This cavity is, again, a structural similarity with the tertiary structure of RNA in group II introns, as shown in Fig. 5 of the paper.
If we want to simplify further, the evolutionary connection between Prp8 and RT proteins rest mainly on weak sequence similarities, that can be shown only by enhanced algorithms, but not by the basic BLAST analysis, and on structural similarities of some domains of Prp8 with some aspects of group II introns structure.
Another important point is that those domains of Prp8, especially the putative RT domain, do not retain their supposed original function in the molecule: neither Prp8 not the spliceosome appear to have any reverse transcriptase activity.
So, what does all that mean, especially form an ID point of view?
I think it is simple enough.
Darwinian evolutionists essentially look at those faint sequence similarities, and at structure similarities, to find possible “ancestors” of a molecule.
That’s fair.
Are those evidences strong enough for Prp8? I am not so sure. However, some evidence exists.
So, could the Prp8 molecule really derive, in part, from some older RT molecule, maybe also some IEP, having retained some of its structural features?
It is possible.
What does that mean from an ID point of view? IOWs, from the point of view of functional information, and of the functional complexity of the molecule, and of course of the whole spliceosome (which includes, of course, more than 100 other different proteins)? What relation has all this with my discussion in this OP?
Very little. And the reason is very simple.
My analysis in the OP is not based on weak homologies that can be seen only with enhanced methods, least of all on structural similarities.
It is based, as said many times, on the huge quantity of sequence similarity that the Prp8 molecule shows from its appearance (in LECA) to humans: in the order of 3000 – 4000 bits, and extremely high sequence identity.
As opposed to no sequence homology at all with any prokaryotic sequence when established by the same procedure (basic BLAST).
Remember, The Latr molecule has no sequence similarity at all with yeast Prp8 at a BLAST analysis: 20 bits, and E value of 7.6. The same molecule retains about 400 bits of information in different bacteria, demonstrating that a lot of sequence conservation is necessary to implement its function.
The yeast Prp8 and human Prp8 share more than 3000 bits of conserved information. Both have no obvious sequence similarity with Latr.
Some could object that basic Blast is not sensitive enough to detect weak evolutionary connections.
Well, but my purpose is not to detect weak evolutionary connections. We are not interested in that, if we are making an informational analysis to detect design.
What we are interested in are huge amounts of functional information which arises at some point in natural history and is then conserved through long evolutionary times.
Prp8, and more in general the spliceosome proteins, fully satisfies those requisites.
Its 3000+ bits of specific sequence information that arise in the transition from prokaryotes to eukaryotes, in LECA, are not present before, and are then conserved for more than one billion years of evolutionary history.
And they are only a small part of the total informational content of the spliceosome.
OK, that was certainly rather complex. But wait for the Chlamydomonas chloroplast psaA mRNA part! 🙂
I think my brain just suffered a spliceosomal event.
Hi all,
Many thanks for your patience. I can see that gpuccio is about done with the many things I have thrown out in this discussion. To help this along, I will try to sum up one tangent so attention may be paid to the main interest here, namely the protein components of the spliceosome.
My own attention on the RNA component of the spliceosome is entirely appropriate, since, as we have learned in this discussion, it is the core of the spliceosome, the catalytic center of the enzyme. in this discussion, we have learned of three versions of this catalytic RNA. One is a single, self-contained catalytic RNA, the group II intron. Another is the set of RNAs that make up the core of the spliceosome. Yet a third, not yet discussed by gpuccio, is typified by the Chlamydomonas chloroplast psaA intron(s). This third example is a split group II intron, in which two separate RNA molecules bind together to form a catalytic RNA. Without more elaboration, I trust that readers can see the the implications regarding the ways in which group II introns may vary, and why, from the perspective of the RNA, the “distance” between group II introns and the spliceosome is not impossibility far. This may be consistent with the implication seen in the preceding that the information content, as it were, of the RNA component of the spliceosome is not very great, and probably not enough to support, from a purely informational perspective, the hypothesis that the spliceosome is a product of design.
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.
Again, many thanks for your patience, and for your continued attention. And special thanks to gpuccio for tolerating my admittedly annoying manner in moving this discussion along.
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
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
(to be continued…)
@162
What does that mean from an ID point of ciew?
What does that mean from an ID point of view?
Arthur Hunt (and all interested):
Thank you for your comment.
“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.”
This seems interesting, and I am looking forward to your further comments. I am very willing to consider your point, but I really need that you make it before! 🙂
Just as a due clarification, I would remind here that I rely on BLAST and long evolutionary conservation to assess information content at sequence level.
#164 Arthur Hunt
Thanks for joining discussion.
“… distant evolutionary relationships or to assess information content.”
First, lets admit an assumption.
1) “..distant evolutionary relationships” assumes materialist only doctrine? Based on what specific
context or mechanism(s)? That rules out Design?
For sake of discussion, lets say it’s a fact. Some self-splicing Introns evolved over time to a Spliceosome. What I hope to see is by what path and Neo-Darwinian mechanism?
2) Evolution does not rule out Evolution by Design(Front-Loading or Pre-Adaptation) unless one A Priori rules it out.
“… rely solely on BLAST… to assess information
content”
3) Of course not. It’s one tool. GPuccio has not
represented it any other way here that I know of. Look forward to other methods, data, or information from you.
4) “Some subunits of the complex I work on defy the logic being used here.”
OK, cannot wait for the great reveal. But as there’s more than one tool like BLAST to describe DNA information, there’s more than one way to infer Design.
From DNA Metadata to coordination and organization of interdepedent systems, life dances to an orchestrated beat. Each unit, subunit a part of a coordinated system. Organized proteins across multiple domains pulled together to form a specific function in many cases, using what was once cast as “junk” DNA to both govern, change and reformulate on the fly at times tied to environmental stimulus. A dynamic system that both reflects on it’s surroundings and acts.
Not to mention information sensing, controlled release, entrances and blocking, sharing, error correction, and cognitive signal processing. In life at all levels from organism to cells internally and externally.
Organized, step-by-step processing, coordinated task unfolding at rapid rates, with dynamic reads, writes and error checking.
A bit off-topic, but very curious where Hunt stands on debates taking place over neo-Darwinism or Extended Theory.
Where btw, ID scientist did attend…
Modern Synthesis – Extend or Blow it up
note for readers: see Table 3 for comparisons of
EES to past standards and Traditional predictions in evolution.
#167 Gpuccio
“I am very willing to consider your point, but I really need that you make it before!”
and preferably a specific link or two on the assertion would help as well 🙂 Telling people to google is a bit trollish. Just give me specifics please.
DATCG:
Thank you for your interventions. I fully agree with your concepts.
I am indeed very happy of the discussion here. It’s exactly what I have always hoped for: a respectful discussion between the two sides about biological details and their interpretation.
So, I am really grateful to Arthur Hunt for stimulating it and taking part.
Like you, I cannot wait for the great reveal. I am sure it will stimulate further interesting discussion and intellectual confrontation. Which is what I do love.
I agree with you that “telling people to google is a bit trollish.” But the reference to Chlamydomonas psaA was very specific, and I had no real difficulty in finding what it was about. I am going to discuss it in my next posts, because it is really weird and interesting.
I really hope that you will stay in the discussion. Your contribution is precious! 🙂
What’s so weird and interesting about that Chlamydomonas psaA?
Is it that it has four propellers around itself, thus proving that drones are the natural result of Neo-Darwinian evolution?
While we anxiously await the big revelation by the distinguished professor Arthur Hunt, it would be interesting to see what gpuccio found about the Chlamydomonas psaA that makes it such a strong case to prove Neo-Darwinism and disprove ID.
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
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
(to be continued…)
Dionisio:
“Is it that it has four propellers around itself, thus proving that drones are the natural result of Neo-Darwinian evolution?”
More or less… 🙂
“it would be interesting to see what gpuccio found about the Chlamydomonas psaA that makes it such a strong case to prove Neo-Darwinism and disprove ID.”
I would not say so. I would rather say that it is a weird system, difficult to understand from any point of view.
I will be more clear in next post.
gpuccio,
Thanks for clarifying that.
Still, after reading what the distinguished professor Arthur Hunt has written here so far, I keep asking:
Where’s the beef?
🙂
Arthur Hunt (and all interested):
So, the famous Chlamydomonas psaA.
A few premises, so that all may follow the discussion (I hope!).
We have already said that group II self-splicing introns are distributed as follows:
a) In bacterial genomes (where they are anyway rather rare)
b) Organelles in lower eukaryotes and plants
They are, instead, absent in eukaryotic nuclear genomes.
In my #119, an answer to Mung, I have also specified:
“In the bacterial genome, it seems that they are mainly localized in less important and less conserved genes, and sometimes in intergenic regions. Remember, introns are however rather rare in prokaryotes.
In organelles, they are more often linked to housekeeping genes, but they are often more or less degenerate, and often they do not have ORFs.”
Now we are going to deal with the b) situation: group II introns in a very important gene in an organelle (the chloroplast) of a lower eukaryote. And degenerate too, in a very special way!
If you are already confused, wait for the rest!
So, let’s introduce our protagonist:
Chlamydomonas reinhardtii
What is it? It’s a single celled green alga, a “simple” form of plant. Here is its Wikipedia page:
https://en.wikipedia.org/wiki/Chlamydomonas_reinhardtii
For various reasons, it is also a model organism, like C. elegans, Drosophila, and others. IOWs, there is a lot of information and research about it.
Now, let’s se the gene:
psaA
The protein is 751 AAs long, and its complete name is:
Photosystem I P700 chlorophyll a apoprotein A1 (P12154).
Its function, according to Uniprot:
“PsaA and PsaB bind P700, the primary electron donor of photosystem I (PSI), as well as the electron acceptors A0, A1 and FX.”
IOWs, it is an important part of Photosystem I, a photosyntetic system.
Quite an important molecule, therefore!
The protein is, of course, located in the chloroplast, the photosyntetic organelle of plants.
It can be useful to remember that chloroplasts are thought to be derived from cyanobacteria through an endosymbiotic event.
Indeed, the psaA protein from the chloroplast of Chlamydomonas_reinhardtii is extremely similar to the same protein in cyanobacteria (best hit: 1337 bits, 1.78 baa, 86% identitis, 91% positives).
Let’s go to the gene.
It can be useful to remember that only a few of the chloroplast proteins are encoded by the chloroplast genome. It is supposed that many of the ancestral cyanobacterial genes of the plastid were transferred to the nucleus or were lost. Only approximately 100 proteins are still encoded in the chloroplast genome, while most of the few thousand proteins of the plastid proteome are encoded in the nucleus and then imported to the chloroplast.
Well, in Chlamidomonas reinhardtii the psaA gene is one of those encoded by the chloroplast genome, but it has a very strange peculiarity: it is split into three separate exons that are dispersed on the chloroplast genome.
That’s some degeneration!
The exons are transcribed separately.
And the introns? There should be two of them, for three exons.
Well, they are fragmented, too. The three exons, indeed, are flanked by sequences which are parts of the original group II introns.
So, each exon is transcribed separately from the others, and each transcript includes the flanking “intronic” parts.
This is strange enough. But even stranger is what happens after that, IOWs the “maturation” of those transcripts to form the final mRNA.
We will see that in next post. 🙂
@175 follow up
For those who aren’t familiar with the question asked @175, this short video may help to understand its contextual meaning:
https://www.youtube.com/embed/R6_eWWfNB54
Dionisio:
Very interesting!
It’s always important to quote our sources, in science. 🙂
@176:
a) In bacterial genomes (where they are anyway rater rare)
rather?
They are, instead, absent in euakryotic nuclear genomes.
eukaryotic?
Chlamydomonas reinhardtii?
Huh?
Who in the world comes up with these names? 🙂
For various reasons, it is also a model organism, like C. elegans, Drosophila, and others. IOWs, there are is lot of information and research about it.
there are is ?
@178:
“It’s always important to quote our sources, in science.”
Yes, that’s exactly how your politely dissenting interlocutors usually do here, don’t they? 🙂
gpuccio:
I second that.
Arthur Hunt (and all interested):
Just a brief update, to answer at least some questions.
Organellar group II introns, as said, are defective. Therefore, they require for splicing the intervention of proteins, nuclear encoded proteins.
IOWs, group II introns in organelles cannot any more effect their own splicing, and so they are spliced by one or more nuclear proteins.
However, if only a single RNA molecule in the transcript is spliced, this is called cis-splicing. It is similar, in a sense, to what the spliceosome does with spliceosomal introns in the nuclear genome, but the protein components are absolutely different.
But there is another form of splicing of group II introns in organelles, and that’s exactly what we observe in our psaA gene in Chlamydomonas. A few examples of this mechanism are known, but the Chlamydomonas psaA is the only one that has been studied in some detail.
The fact is that, as we have seen, psaA is not only degenerate, but also fragmented, and dispersed in the chloroplast genome. Not only the three exons, but also the two group II introns are fragmented, and parts of them flank each of the three exons.
As each exon is transcribed separately, with its flanking parts, we have at that point three different transcripts. So, the nuclear proteins that accomplish the maturation of this fragmented pre-mRNA have to do two different things:
a) Reconstruct an appropriate pre-mRNA from the three transcripts, so that the final result contains the three exons and the two reconstructed introns
b) Splice the two introns, generating the mature mRNA
Rather amazing, isn’t it?
This form of splicing is called trans- splicing, because it acts on different transcripts joining them. As said, our psaA is the best known, but not the only, example.
Add to that that another gene takes part in the reconstruction: it is called tscA, and it is a gene in the chloroplast genome that does not encode for a protein, but for a short RNA sequence.
The tscA transcript is essential to complete the reconstruction of the introns, but to do that it must be processed by the nuclear proteins that assist in the splicing.
In a sense, tscA is the last piece of the puzzle, which must be inserted to reconstruct the introns before their splicing.
I will stop here for the moment. I hope you get the picture.
However, there are still a few aspects of the matter that are even more amazing. To next post. 🙂
@176:
Wow! now I see why you said that it is weird and interesting.
@182:
Amazing is an understatement.
The step a) must guarantee the correct sequence of connected transcripts, right?
How’s that achieved?
Do the separate transcripts have something that identifies each of them as either ‘first’, ‘second’, or ‘third’?
Perhaps it’s obvious, but I don’t see it.
Yeah, right. 🙂
If this were a ballet choreography, dancers would struggle trying to remember what to do at every moment in synch with the music. What a chaos.
But the cells figured out how to do it right.
@182:
Wow! That’s quite weird indeed.
@182:
Can’t wait to watch the next episode. The plot keeps thickening. 🙂
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
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
(to be continued…)
@146:
“The Spliceosome: The Ultimate RNA Chaperone and Sculptor”
(paywall)
Check this out:
http://europepmc.org/abstract/MED/26682498
http://europepmc.org/articles/.....pdf=render
Arthur Hunt:
That may or may not be true but it still remains that there isn’t any non-telic account for those RNAs’ existence.
As Dr. Behe once said:
So it is for the spliceosome
Some interesting papers listed @10, @12, @31
Here’s one:
Lights, camera, action! Capturing the spliceosome and pre-mRNA splicing with single-molecule fluorescence microscopy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990488/pdf/nihms806199.pdf
Some interesting papers listed @10, @12, @31
Here’s one:
The nuts and bolts of the endogenous spliceosome
http://onlinelibrary.wiley.com......1377/epdf
Juicy!
Structural biology of the spliceosome
Structural studies of the endogenous spliceosome – The supraspliceosome
Lots of yummy cookies in this jar:
http://www.sciencedirect.com/s.....125/supp/C
ET:
As I have said, the RNA component of the spliceosome is amazing in its own right. Especially if we consider that the original functional RNA molecule, the group II self-splicing intron, is fragmented, transformed, coupled to many proteins, reconstructed.
But, of course, in terms of mere sequence content in the RNA sequence, the functional information is big but not huge. Probably in the order of a few hundreds of bits.
That could probably be enough to argue for design, but I prefer better margins, and with the protein component I think we have a safer case.
You may wonder why I stick to the information content of individual molecules, especially proteins. Of course there is a lot of meta-information beyond that, and I would like very much to argue for it, too: the interactions, the irreducible complexity, the regulations, and so on.
But I stick to protein sequences for two simple reasons: I have a definite way to approximately measure functional information in them, at least in specific cases, and the functional information I find at that level is so abundant that it already allows to make a mind-blogging argument for design.
#171 Gpuccio,
Agreed, as am I glad for Arthur Hunt’s appearance. The more the merrier.
My concern is to highlight reference papers Arthur himself approves and uses as guidance. I’ve reviewed briefly(read in part) and read in whole some of the papers offered by others here. Along with my own search on evolutionary scenario for the Spliceosome.
And while I enjoy any insights given, what good does it do us all if left to our own interpretations? Or, maybe not seeing a paper he would recommend for reading?
I like details. Without the details, to many assumptions are left standing.
I desire to read what Arthur thinks is important. What are the relevant document(s) in regards to evolutionary history of the Splieocome?
I want to know I am reading the same information. So a paper or 2 he recommends is important I think to clarify specifics on such a subject of evolution as there are several papers on the Spliceosome history.
And yes, look forward to more by Arthur and your discussions 🙂
Glad to see this develop. I know you put a lot of time into this. As well as Arthur having a busy schedule. So do I, thus a need for specific papers 🙂
Thanks Gpuccio again and to Arthur for responding.
#111 Mung, Gpuccio 118,119 nice…
Here’s another paper I reviewed a few days ago. Do not think it’s posted. Published 2010 from BMC…
Evolution of spliceosomal introns following endosymbiotic gene transfer
Endosymbiotic Theory… Lynn Margulis pops up:
Or, SymbioGenesis
Dionisio:
Wow! You find a real treasure trove! 🙂
DATCG at #195:
Very interesting paper indeed.
And look at what Dionisio found at #192! 🙂
All this new information will certainly find some important role in the following discussion.
Arthur Hunt (and all interested):
First of all, I want to give some reference about the psaA topic. One of the best and most recent papers is the following:
A Ribonucleoprotein Supercomplex Involved in trans-Splicing of Organelle Group II Introns
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087748/pdf/zbc23330.pdf
Open access.
A few important considerations.
a) All this issue of organelle splicing and especially trans-splicing is very complex, and many things are still not understood. For trans-splicing, the best model is still psaA. I will state just from the beginning that IMO we still know too little to draw appropriate conclusions. However, I will try just the same to outline the problems, and some proposed “explanations”.
b) As you can see in the paper I referenced, there is a small group of examples of trans-splicing in chloroplasts (see Table 1), and another group of cases in mitochondrial genes (Table 2). For the moment, I will focus on psaA in chlamydiomonas. But I will make a first important general comment here: this small group of genes seems to show that the cases of trans-splicing are very different one from the other: different genes, different fragmentation, probably different proteins involved. With some similarities, as we will see.
c) Even if we know a limited number of cases, and most of them only approximately, trans-splicing could be more frequent than presently understood. However, it seems to involve, practically always, important genes, so its role cannot be underemphasized.
OK, now let’s deal with psaA, and add some important information about it. In next post.
gpuccio,
The more we know, more is ahead for us to learn.
This fascinating topic that you’ve brought up for discussion, starting with an excellent OP that’s followed by a very comprehensive series of insightful comments (mostly in response to professor Arthur Hunt’s inputs), has motivated me to search for additional information that could shed more light on what is known about this amazing biological machinery and its functioning.
But I have to admit that the available information is becoming so overwhelming by its increasing volume, that sometimes I lose track of the papers. This happens with other biological topics too.
The Big Data problem they have been talking about for the last several years seems to get worse with the avalanche of research discoveries made in wet and dry labs out there.
The free Zotero tool may help to alleviate the problem, but discipline is still required to avoid skipping important papers after having been located. Zotero also helps to prevent repetitions. My lack of constant discipline has mace me lose track of interesting papers I had located before. It’s frustrating to realize that my laziness has led me to squander time I had spent searching for information.
It’s encouraging to see that sometimes you may use some of the papers that have been found. That motivates me to try better next time.
Arthur Hunt (and all interested):
The first question is: how complex is the trans-splicing of psaA in Chlamydiomonas?
Of course, the description I have already given of the process seems to imply great complexity. But what is, in detail, the role of the protein component?
Unfortunately, even for this deeply studied case, we know probably too little. But something we know.
The paper I have referenced here, which is of 2016, makes a good summary of what is known, and adds a lot of original information.
Let’s start with this very good summary of the main premises, which I have in some way already provided:
I will anticipate here that much of the interest in these trans-splicing complexes is that they are thought to be some model for the origine of the spliceosome. In that sense, they are certainly related to our main discussion.
But how complex is the trans-splicing machine for psaA?
In previous works, at least 14 proteins were thought to be implied, but only 7 of them have really been identified.
We will go back to these proteins later.
The role of many of these proteins has been assessed because specific mutants showed impairment of photosynthesis.
It was also supposed that those proteins acted in the form of some high molecular weight complex. However, the referenced paper has for the first time given evidence of that.
As an image is better that a thousand words, let’s look at Fig. 1, which gives in B and D a gross scheme of the two subcomplexes, and in A and C a list of the core components of each of them. Raa1 is a big protein which seems to have an important role in both subcomplexes.
The paper also confirms the important of the “missing piece”, the tscA gene, in completing the structure of intron 1, and the intricate role of the proteins in the subcomplexes to help the maturation of this small RNA molecule.
But what do we know of the 7 proteins that have been so far characterized?
If you look again at Figure 1, the lists in A and C, you can find some important information in the column “description”. For many of them, no functional annotation is available (IOWs, no known domains have been identified in the sequences). A couple of them show some known domain homology (for example, Raa2 has a pseudouridine synthase domain, for some reason that is not shown in Fig. 1, but you can find the information in Fig. 4). However, the most common domain found in them is the OPR sequence, an Octatricopeptide repeat sequence probably implied in RNA binding. Pentatricopeptide repeat sequences are also implied in other cases of trans-splicing.
The general idea is: these proteins are, at least some of them, rather isolated proteins. For example, the very big Raa1 protein (2103 AAs), if blasted, shows only 4 low homology hits (107 -352 bits), all with green algae organisms.
IOWs, these are not widely conserved proteins. Not at all. As far as we know, they are rather organism specific proteins, with some low homology to a few existing domains.
A lot of further details can be found in the paper, but I will not deal with them here.
So, as the result of all this information, I would like to highlight a few points:
a) The complexity of the system is apparently very high, and nobody seems to deny that, even if we still miss a lot of information to really understand it as a whole.
b) One amazing aspect of this system is how specific it seems to be. Indeed, as far as we know, it is specific not only for the organism Chlamidomonas reinhardtii, but also for the psaA gene. But there is more: it is specific for each of the two introns in that gene: indeed, many proteins are involved only in the splicing of one of the two introns.
c) Finally, this amazing system seems to be made mainly of specific proteins that we find practically only in this organism.
I hope you are as amazed as I am.
There is a final important point to illustrate, and I will do that in next post.
Arthur Hunt (and all interested):
Another aspect about psaA is related to the following paper:
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
I will try to make it simple.
In the introduction, this paper gives us an important piece of information:
OK. Let’s remember that.
Then comes some information that we already know, but it can be useful to refresh it:
Then the paper briefly discusses two possible theories to “explain” the complexity of the trans-splicing system we are discussing (psaA and other similar cases).
As I have already pointed out, nobody here is doubting that complexity. The system appears to be complex, everyone is rather certain of that.
But how can we explain that complexity? What is the reason for it?
I would like to emphasize that the main question, in this discussion in the paper, is not so much “how”, but rather “why”. Why did such a complex system originate? Why is it necessary?
Of course, they also say something about the “how”, as we will see later.
This discussion is interesting, because of course everyone of us is probably wondering, at this point: why such a complex system? For one specific task?
And of course, that kind of discussion, at least in a very general sense, can also be used as a starting guide to debate the spliceosome itself (I will try later to point at the important differences, however).
So, the authors of the paper give a clear and simple summary of two possible theories about the “why”. I will try to simplify them even further here, but if you want you can read their words directly in the paper, in the two paragraphs that start with:
“There may be multiple reasons for the remarkable complexity of chloroplast RNA metabolism.”
Essentially, the two theories are:
a) The complexity is needed for adaptational or regulatory reasons. We can call this theory the “regulatory” theory. The complexity offers tools to change the working of the system in response to different situations.
b) The complexity arises simply to compensate for random errors in the genome, in particular the degradation of the original DNA (fragmentation, transformation, loss of function). The authors call this the “spoiled kid hypothesis”, where the spoiled kid is the degenerate DNA of the gene, and the mutations in the nuclear genome which compensate for that degeneracy are called an “evolutionary ratchet”. IOWs, in this theory the complexity that arises to compensate for the degeneracy has one purpose only: to compensate for the degeneracy.
Theory a) is clear enough. It is usually the theory applied to many complex systems, including the spliceosome, whose many regulatory functions have been well demonstrated. One form of the theory, however, assumes that the spliceosome originated as a ratchet, and then evolved new functions. But of course it is possible that both the compensating function and the regulatory function were developed at the same time.
In theory b), instead, there is no regulatory function. The system is only a ratchet. It serves nothing else.
(By the way, I am not responsible for the “ratchet” analogy, it is in the paper, and not only in this one)
Is everything clear?
Let’s stop just a moment. To next post.
@198:
The plot thickens…
This discussion is getting better with every comment posted.
And some of us here are learning much from it.
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
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
(to be continued…)
(sarcasm alert with respect to the spliceosome)-
But it’s all material processes using physical material. There isn’t anything magical going on, just plain ole physics and chemistry.
(sarcasm alert with respect to the spliceosome)-
But it’s all material processes using physical material. There isn’t anything magical going on, just plain ole physics and chemistry.
@200 & @201:
As usual, very thorough attention to details explained with much pedagogy.
This discussion could be a valuable chapter if a biology textbook for post docs.
The complexity of the described issues is so visible that one gets dizzy trying to follow the whole explanation for the first time. Several rereads might be required for the penny to drop.
It seems like gpuccio has rolled up his sleeves and gotten to work hard on this.
Many of his readers (myself included) are benefiting from his effort.
Thanks.
ET @204 & 205:
Of course, that’s just pure physics.
Is there another option?
🙂
@200:
That functional complexity is just an illusion.
We just don’t understand evolution.
🙂
Dionisio @ 203: You set the bar very high, my friend.
Arthur Hunt (and all interested):
Now, before going to the experimental part of the paper reference at #201, let’s say still something about theory b): the ratchet theory for psaA trans-splicing.
As we have seen, this theory assumes that mutations at the level of nuclear genome (what they call “suppressor mutations) “compensate” for the alteration in the chloroplast gene (the “spoiled kid”).
So, in this case, the compensating “suppressor mutations” would be those which generate the many proteins in the nuclear genome which effect the trans-splicing, while the “spoiled kid” is the degenerate and fragmented psaA gene in the chloroplast genome.
But there is a problem. If the degeneracy of the gene (for example, being fragmented into three separated exons/intron-parts, plus a small RNA coding gene) is such that it prevents completely an important function (photosynthesis), IOWs if the spoiled kid is really and severely spoiled, the organism should be subject to strong negative selection, and there is no evolutionary time to “wait” for the compensating mutations to provide the complex solution.
In the words of the authors:
What does this mean?
It means that they are proposing a new sub-theory, called CNE. That theory is not really new. We find a good summary of it, more in general, in the abstract of a paper of 2011:
How a neutral evolutionary ratchet can build cellular complexity
http://onlinelibrary.wiley.com.....9/abstract
To say it simply, in cases like the psaA degeneracy, where survival does not seem likely without some remedy, the remedy must be already there, at the time when the kid becomes spoiled. So, the idea is that neutral evolution provides the new information in advance, so that it is ready to act when the situation required it. That’s probably why they call that neutral evolution “constructive”! 🙂
So, going back to our psaA, when the chloroplast gene becomes fragmented and degenerate (which, frankly, does not seem an event which should require a lot of time), the 14+ proteins that will effect its trans-splicing are already there, kindly arranged by “constructive” neutral evolution.
I know what you are thinking… 🙂
In the words of the authors of the paper referenced at #201:
Did they say “co-opted?”. Yes, they did!
OK, no problem in that, I suppose. After all, it is a “pool” of potential compensating proteins. Maybe a lot of them, who knows?
And after all, they only have to recognize the trascripts from four different genomic sites, reconstruct a complex RNA structure from them, and in some way correctly effect the splicing. Where’s the problem?
And for those who are tired of Behe’s old concept of “irreducible complexity”, we have here a brilliant, new and certainly more fashionable concept:
Irremediable complexity!
IOWs, a complexity which should not be necessary, but becomes “irremediable” because of serious, unavoidable events (spoiled kids, which, as each parent knows, can cause a lot of trouble).
OK, no comment for the moment. We still have to look at the experimental part of the paper:
On the Complexity of Chloroplast RNA Metabolism: psaA Trans-splicing Can be Bypassed in Chlamydomonas
In next post.
Arthur Hunt (and all interested):
The experimental part of the paper is simple enough and clear enough, and it aims essentially to demonstrate that, at least in the case of psaA, theory b), the ratchet theory, is probably true.
And I must say that their argument is of some interest.
Our model organism, Chlamydomonas, is very good for getting mutants.
So, they took three different mutants, one for each of the three proteins raa1, raa2 and raa3. As expected, each of these mutant was defective at photosynthesis, because of the defective psaA trans-splicing.
Of course, according to what we have already said, in the raa1 mutant the splcing of both introns was compromised, while in raa2 mutant only intron 2 was involved, and in the raa3 mtant only intron 1.
Then they inserted into the chloroplast genome of the three mutants an intron-less version of the psaA gene.
The simple result is that photsynthesis was rescued in all three mutants.
But there is more: they compared the behaviour of the “rescued” mutants with the Wild Type, and they could not observe any difference.
The comparison was made not only in standard conditions, but also in some stress conditions: iron deprivation, competitive growth, high temperature, low oxygen. In all these settings, growth and behaviour of the rescued strains and of the WT were not different.
They conclude, therefore that theory b) must be true: the trans-splicing system, however complex it is, has apparently only the purpose of trans-splicing the degenerate psaA gene. If we provide the organism with an intron-less gene, it is no more necessary.
Now, this is very interesting, and I don’t want in any way to underemphasize these results, which I have tried to report as simply and clearly as possible.
I will add, however, a couple of cautionary notes:
1) Test in the lab of the relative fitness of different populations should be considered with some caution. Of course, in the wild and in long evolutionary times a lot of differences could be revealed which cannot be apparent in a short test under controlled conditions. This is true for all these kinds of tests. IOWs, it is still possible that the trans-splicing system has regulatory functions which could not be observed in the tests made during the experiment.
2) Let’s remember that we still have a very limited understanding of this system. I would reasonably wait for further information about the proteins involved, the structure, the molecular function, and above all the similarities and differences between different trans-splicing systems in different organisms, before drawing final conclusions about this complex issue.
That said, I frankly admit that these results, taken as they are, are in favour of theory b) for this specific system.
Which makes the system itself, as we understand it at present, a really weird object from all points of view.
Many more things could be said about this aspect, but I will stop here for the moment, and leave some space to a possible discussion.
In next post, I will rather outline the (few) similarities between this trans-splicing system and our spliceosome, and the (many) differences.
And maybe add some interesting recent information about the spliceosome itself.
Arthur Hunt (and all interested):
Just an add-on to the previous post.
For those who liked the concept of irremediable complexity, there is more.
From the Introduction in the same paper:
(emphasis mine)
And from the Discussion:
(emphasis mine)
As you can see (I repeat myself) nobody here is denying the complexity. But this fascinating type of complexity is now labeled as both irremediable complexity and futile complexity.
Behe will probably be envious! 🙂
CNE? That one cracks me up. Molecules just diffuse throughout the cell and if they happen to meet another and join then that’s just wonderful if it makes something useful. It isn’t as if those molecules had something to do on their own or some other molecule to link up with. They just happened to be there and meet up with a mate.
Larry Moran is a fan of constructive neutral theory. To me it’s just another just-so story.
Tornado in a junkyard, anyone?
ET:
Shall I say it?
OK:
CNE is rubbish! 🙂
“CNE is rubbish!”
That’s so rude. 🙂
TWSYF @209:
gpuccio is who has set the bar too high for his politely dissenting interlocutors.
I’m just trying to make it easier for the rest of us to keep track of the interesting discussion GP is having with a distinguished professor.
BTW, gpuccio posted three additional comments that render the info @203 incomplete.
I’m awaiting the breakthrough revelation that professor Arthur Hunt promised.
gpuccio:
Clear as chloroplaster!
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
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
(to be continued…)
TWSYF @209:
@216 follow-up
You may want to read the comment @206.
So CNE includes some kind of co-option too?
Hey, why not?
At least it sounds important.
🙂
Irremediable complexity?
It sounds important, doesn’t it?
🙂
How about complex functionally specified informational complexity?
Chuckles 🙂 OK, that was funny. Thanks for the continued reviews Gpuccio and digging on your part!
Irremediable Complexity was briefly addressed by Michael Behe in 2011…
Brief Review of Irremediable Complexity and CNE by Behe
Note: its from 2011. I’m sure more experimental work has been done since to “support the feasibility of the model.”
see references 3 and 4 above at the linked article
(voila) emphasis mine
Or at least so the story goes. Is it plausible? As as neo-Darinian tale? Maybe. But with more details I hope.
I’ll leave the rest of the review for readers to pursue.
DATCG:
Thank you for the link! 🙂
I did not know that Behe had already touched tose points, and so brilliantly, otherwise I would certainly have quoted him!
Luckily, you have provided the reference.
I am really happy to be, once again, in perfect accord with what Behe says. 🙂
GPuccio, the article by Behe. You might appreciate the lead line. 😉
DATCG:
Yes, the interesting part is that, as I have tried to emphasize, nobody denies the complexity.
And nobody denies that the complexity works, that it is indeed functional.
So, according to these people, we have:
Irremediable futile functional complexity
The concept of the century! 🙂
DATCG and gpuccio,
Let’s not rush to conclusions before reading the breakthrough revelation that professor Arthur Hunt promised.
Let’s be patient.
🙂
No matter how persuasive the CNE might be, I still prefer Cinderella’s fairytale, because it makes more sense from a rational perspective: a pumpkin was converted into an elegant carriage, mice became beautiful horses, a grasshopper was hired as the cochero.
🙂
Is CNE in the “third way” arsenal?
Irremediable complexity ?
See the 112 papers citing the featured paper:
https://www.researchgate.net/publication/47755596_Irremediable_Complexity
See the papers referenced in this paper:
… However, the very different mechanism of the RNA editing systems in existence, and their very limited distribution within specific groups of organisms indicate that they are more likely derived traits that evolved later in evolution [65,66]. The sheer complexity of the kRNA editing process, with no obvious selective advantage, led to the proposal that insertion/deletion editing arose via a constructive neutral evolution (CNE) pathway [67]. Indeed, RNA editing in trypanosomes is always mentioned in support of CNE as an example of how seemingly non-advantageous, complex processes can arise [68,69]. …
PLOS NEGLECT TROP D
Laura E. Kirby, Donna Koslowsky
DOI: 10.1371/journal.pntd.0005989
https://www.researchgate.net/publication/320295574_Mitochondrial_dual-coding_genes_in_Trypanosome_brucei
Gpuccio,
Pardon the pun, but an Intronic Interlude while awaiting Arthur’s next comment?
What of Introns? Once deemed as “junk” DNA. I’d looked at them in past specifically for potential signs of function and design. Documentation on new functions of Introns is growing. Another angle, but still coordinated with careful splicing and targeting by the Spliceosome.
Not to distract from this post.
Looking forward to Arthur’s follow up. But maybe in future, if not you, someone here @UD could keep track on Intron’s functions and possible dual role relationships? Maybe that’s stretching it a bit 😉 But something’s missing.
We’re getting the splice events for mRNA, but also producing ciRNAs or other noncoded RNAs.
From alternative splicing to Circular Long Noncoded RNAs – ciRNAs. Some reside in the nucleus, others in cytoplasm.
Is there added constraint on Spliceosome as a result of Intron functionality? As in wrong splice, wrong dice. How much room for a mistake is there?
Circular RNAs are more stable than linear. I suspect more will be found.
For anyone who wants something to read, General overview of current progress…
Introns: The Functional Benefits of Introns in Genomes(from 2015)
more…
Agreed… Addressable subspace must be tightly controlled, otherwise it’s all downhill and access is lost. Creating a cascading roll of errors until ending in catastrophic event, or removed by error correction.
Arthur Hunt (and all interested):
The interest for group II introns trans-splicing (or even cis-splicing) in organelles is in part connected to the idea that these scenario could be considered as a model of the evolution of the spliceosome.
That idea is more or less as follows:
a) Group II introns in bacterial genomes are usually self-splicing. They are relatively autonomous retrotransposon entities, and they use their intrinsic ribozyme activity to self-splice and retro-home.
However, even in this simplest scenario the intervention of a protein is necessary, but it is the IEP, a protein encoded directly by the intron itself.
b) When group II introns are found in eukaryotic organelles, however, they are usually degenerate, and lack the ORF for the IEP.
As a consequence of that, apparently, they need the intervention of other proteins, proteins encoded in the nuclear genome of the eukaryote, to be spliced.
c) Such splicing can happen both in cis (the proteins act on one transcript) or in trans (the proteins act on different transcripts, that need to be reconstructed. The second scenario (trans-splicing) is necessary when the original gene has been fragmented, and the individual parts are transcribed separately. Of course, trans-splicing is more complex than cis-splicing, and it seems to involve more complex multi-protein structures. psaA, that we have discussed in detail, is the best model for this kind of scenario.
d) Finally, the eukaryotic nuclear genome lacks group II introns, but is repleted with spliceosomal introns. The splicing of these introns requires a very complex structure, our major spliceosome (except for some rarer froms of introns, which are spliced by the moinor spliceosome).
e) So, the idea would be that trans-splicing, with its discreetly complex multiprotein structures, could be considered an indication of how the spliceosome itself evolved, especially if we accept that spliceosomal introns evolved from group II introns when they invaded the nuclear genome of eukaryotes.
Now, I will try to show what are the similarities between the two scenarios (trans-splicing and spliceosomal splicing), and then what are the differences.
Similarities:
1) The main common feature is that the intron is spliced by some complex multi-protein structure, and that the proteins are encoded by the nuclear genome.
2) The second common feature is that the catalytic activity of the splicing is essentially implemented by the RNA component, which retains a similar structure, even if constructed in different ways.
I would like to specify that this point is more obvious for the self-splicing of group II introns and spliceosomal splicing. I have not really found details on how the catalysis takes place in trans-splicing, but I imagine that the RNA component may have an important role there too.
OK, that’s all about similarities, IMO. Now let’s go to the:
Differences:
1) Specificity vs universality.
Trans-splicing, as we have seen, is very specific. The multiprotein structure that effects the reconstruction and splicing of psaA seems to act only on that gene. Moreover, as we have seen, different proteins are neede for each of the two introns.
On the other hand, the spliceosome is highly universal. It is very similar in all eukaryotes, and all spliceosomal introns are spliced by the same spliceosome (even if with the great flexibility allowed by the basic structure).
2) Difference in function:
Trans-splicing does two different things: it reconstructs the fragmented gene, even participating in the maturation of its parts, like the tscA RNA; and then it effects the splicing of the two introns.
The spliceosome does only the splicing, but with all the additional complexity linked to the differences in intron length, sequence and structure, and to alternative splicing and other regulatory processes.
Moreover, group II introns are deeply different from spliceosomal introns, even if they could be derived from them. Gorup II introns are rather variants of a similar structure, while spliceosomal introns vary a lot in length, splicing sites, added functions, and so on. Spliceosomal introns also lack any catalytic and retrotransposon activity. That’s why the catalytic splicing is “demanded” to the 5 snRNAs in the spliceosome.
Finally, if we believe to the meaning of the results presented in post #211, the trans-splicing system seems to serve essentially for splicing, and could not have additional regulatory functions. The additional regulatory functions of the spliceosome-spliceosomal introns system, instead, are beyond any doubt.
3) Difference in conservation:
Both the trans splicing complex and the spliceosome are essentially eukaryotic structures.
However, while the psa trans-splicing complex is made of proteins that could well be defined as “taxonomically restricted” to that organism, the proteins which make up the spliceosome are, as we have seen, extremely conserved in all eukaryotes.
To illustrate this point, I will present here two blasts from two proteins, both of them from Chlamydiosomam reinhardtii:
a) Raa1 is probably the main structural protein in the trans-splicing process. I have blasted it against all known sequences in the non redundant protein database of NCBI (practically all know proteins). Here is the result:
Protein Raa1 from Chlamydiosomam reinhardtii (Q5K4K9)
Length: 2103 AAs
Blasted against the whole protein database:
Only 4 hits:
Volvox carteri f. nagariensis (colonial green alga)
487 bits 318 identities
Gonium pectorale (colonial green alga)
352 bits 272 identities
Monoraphidium neglectum (single-celled green alga)
171 bits 175 identities
Gonium pectorale (colonial green alga)
152 bits 208 identities
That’s all. A really taxonomically restricted protein.
b) Of course, Chlamydiosomam reinhardtii is not only the proud owner of the most studied trans-splicing complex. It also owns a spliceosome, like all eukaryotes.
So, I have blasted the Prp8 protein, which is the main structural protein in the U5 subunit of the spliceosome, vs the most “distant” eukaryotic group: vertebrates. Here are the results:
Protein Prp8 from Chlamydiosomam reinhardtii (A8HPL0)
Length: 2346 AAs
Blasted against vertebrates:
First 100 hits:
Best hit: Patagioenas fasciata monilis (bird)
4040 bits 1889 identities
Lowest hit (among the first 100): Clupea harengus (bony fish)
4013 bits 1878 identities
A truly universal protein. More than 4000 bits of conservation between green algae and vertebrates. Remember, about 1 billion years.
And the amazing thing is the consistency of conservation: only 27 bits of difference between the best and worst of the first 100 hits in vertebrates!
With more than 80% identity, this sequence remains practically the same in all contexts!
So, these are IMO the main similarities and differences between the two scenarios: trans-splicing and spliceosomal splicing. Everyone can make up his mind about the possible meaning of trans-splicing as a “model” for spliceosome evolution.
As for me, I would simply say that they are two very different systems with some similarities. Each of them is highly complex, even if the spliceosome is certainly much more complex.
Moreover, the complexity of the splicesome can be approximately and reliably measured through the high conservation of its protein components for extremely long evolutionary times.
The complexity of the trans-splicing system, instead, although intuitively obvious, cannot be really assessed, for two important reasons:
– we know too little of the detailed structure and biochemical function
– the proteins are taxonomically restricted, and therefore we can infer nothing about their functional information from conservation.
DATCG:
Fascinating issues indeed. I fully agree with you.
I hope we can touch some of them in this discussion, if some time is left! 🙂
#231 Gpuccio nice summary.
I’m not so sure about the “invasion” story, but willing to listen.
Wadda ya know, they reference Koonin. Does he ever sleep?
The Intron Invasion! Published 2010
I look forward to Arthur’s rejoinder 🙂
gpuccio: I am really happy to be, once again, in perfect accord with what Behe says.
You should be. You are just a Behe sock-puppet.
Mung:
“You are just a Behe sock-puppet.”
It’s still an honour! 🙂
Arthur Hunt is very knowledgeable with respect to biology. That said he, like all evolutionists, doesn’t have any idea how blind and mindless processes could have produced the spliceosome. As I eluded to earlier all evolutionists for whatever reason think that if something can be described in physical terms, ie physics and chemistry, then clearly materialistic processes produced it. So they always revert to that- “Look we can observe it happening and it is in accordance with physics and chemistry. Case closed.”
That is their entire argument.
Michael Behe is a true hero of our era. Love the guy.
ET @ 236: Excellent points.
ET @236:
Computer software programs operate on pure physical processes -electronic circuits- therefore they must have originated from physical processes. Is that right?
DATCG @230:
The authors of the paper you referenced could be uneducated pro-ID Korean folks who don’t understand evolution. 🙂
Let’s not rely on pro-ID sources to get information from. 🙂
Dionsio@ 238- Of course computer software programs originated from physical processes cuz we originated from physical processes. See? That was easy-peasy. 😎
Seriously THAT is the argument. 🙄
ET @240:
Exactly. You’ve got it right. 🙂
Now we’re on the same page on this topic. 🙂
Poor gpuccio keeps having that weird “functional complexity” illusion and has come up with a convoluted algorithm to quantify it at the protein level. 🙂
Maybe the breakthrough revelation promised by professor Arthur Hunt will finally persuade our friend to change his mind on the subject? 🙂
PS. BTW, does anybody have a clue when we are going to see professor A. Hunt’s next comment posted here? Could that still happen this year? 🙂
Arthur Hunt (and all interested):
Just to demonstrate that we never know enough.
A recent paper, signaled by Dionisio at #192, seems to revolutionize, in some measure, what we know of the spliceosome:
Structural studies of the endogenous spliceosome – The supraspliceosome
http://www.sciencedirect.com/s.....via%3Dihub
Paywalled.
Here is the abstract:
I will try to sum up the main facts and models detailed in this paper. We should take them with some caution, but they are certainly extremely interesting.
a) What we know about the gradual assembly of the spliceosome comes from in vitro studies.
b) The authors of this paper have used new techniques to study the spliceosome in its natural context: in the nucleus of cells.
c) The results are rather amazing. In vivo, the spliceosome would work in a mega configuration, made of four individual spliceosomes, connected by a pre-mRNA.
d) The authors call this structure “supraspliceosome”, and each individual spliceosomal unit “native spliceosome”.
e) The supraspliceosome has a molecular weight of 21 MDa, while each native spliceosome is 4.8 MDa.
f) Differently from what is known from in vitro assembly, each unit of the supraspliceosome (native spliceosome) contains all the five U ribonucleoproteins at all times.
g) The supraspliceosome is assembled before the splicing.
h) Each supraspliceosome includes one complete pre-mRNA, which can be of whatever length or number of introns. Even short pre-mRNAs (like two exons and one intron) are enough to assemble the supraspliceosome.
i) The supraspliceosome seems to splice 4 introns at a time, and after that the pre-mRNA is thought to undergo a process of rolling.
j) The supraspliceosome has important and complex regulatory functions:
Very interesting, isn’t it? 🙂
The Supraspliceosome — A Multi-Task Machine for Regulated Pre-mRNA Processing in the Cell Nucleus
Author links open overlay panel Kinneret Shefer a, Joseph Sperling a, Ruth Sperling b
https://doi.org/10.1016/j.csbj.2014.09.008
Computational and Structural Biotechnology Journal
Volume 11, Issue 19, September 2014, Pages 113-122
https://www.sciencedirect.com/science/article/pii/S2001037014000348
https://www.sciencedirect.com/science/article/pii/S2001037014000348/pdfft?md5=21d9c3c06c61fa29987e17e840819804&pid=1-s2.0-S2001037014000348-main.pdf
https://pdfs.semanticscholar.org/f461/418c3e6be7f3b809adb84ab5cede7d1c9007.pdf
The same authors of the 2017 paper referenced by gpuccio @242 coauthored the 2014 papers referenced @243 & @244.
The newer paper may contain new information obtained in the 3 years after the older papers were published.
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
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
(to be continued…)
#242 Gpuccio
Very interesting 🙂
Thanks for giving a review of whats behind the wall.
#239 Dionisio, sad days when scientist must worry their careers are in jeopardy for daring to question Darwinism and/or conjecture of finding Design. Take religion out of it. Simply recognizing Design is grounds for firing, run out of office, locked out, entire careers over. The Orwellian Thought Minders seek to punish, not just oppress free thought. So much for “free thinkers.” What’s so radical about seeing design? In this instance, the 1st Intron? It’s astonishing to dismiss it out of hand without serious consideration. It immediately reminded me of hardware/software storage requirements for media, search and information exchange. Can there be some criticisms elsewhere? Sure there can. But most storage and retrieval methods require formation of “marks” and/or “introns” for dynamic access, including headers, pointers and significant indexing. All interspersed through out the “randomly” distributed Metadata. There are different requirements based upon load distribution and purpose of systems. Thus differences across prokaryotes and eukaryotes for splicing and/or storage/retrieval access methods.
#245 Diniosio, thanks, will review! Was hoping to read the latest before running into paywall, but these will get me up to speed.
The one thing we have overlooked is the fact that both splicing and editing require knowledge– meaning they just don’t happen. There has to be knowledge of what to splice and edit- on how to splice and edit- etc
ET @248:
Exactly. What, how, when, why?
Dionsio- It’s amazing what evolutionists have to ignore in order to remain loyal to the blind watchmaker. If ever there was a concept based on ignorance it is evolution by means of blind and mindless processes
Connecting the dots: chromatin and alternative splicing in EMT
Jessica A. Warns, James R. Davie and Archana Dhasarathy
Biochem Cell Biol. 2016 Feb; 94(1): 12–25.
doi: 10.1139/bcb-2015-0053
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704998/pdf/nihms708121.pdf
ET @250:
I understand their condition, because I’ve been there, done that.
Unfortunately, as we grow older, we lose our sense of wonder. We stop paying attention to details. Eventually we don’t care about the contextual meaning of words. Our condition degenerates to the point that we don’t understand the meaning of our experiences because we don’t care about it. Then, we don’t care about factual evidences and we don’t pursue truth. It’s a miserable condition that could be described as “anyway, whatever”.
No amount of academic education or intellectual capacity can free one from such a pathetic condition.
What is amazing is that I’m not there doing that anymore.
Now I enjoy watching my little grandchildren being fascinated with little things. I pray that they don’t lose that beautiful sense of wonder.
I would like to teach them to test everything and hold what is good. But that doesn’t mean to try everything. How can they test without trying? They’ll need wisdom. Where can they get it from? That’s what I want to show them.
Dionisio (and all interested):
Very interesting paper at #251.
Of course, all regulatory processes with the “alternative” qualification must be supra-regulated by epigenetic changes.
Indeed, if something can be done in one way or in some other, alternative way, there must be a reason fro that choice. Of course it could also be a merely random choice, but in that case we could scarcely expect working systems at all.
So, epigenetics is supposed to supra-regulate transcription, alternative splicing, and many other regulatory networks.
We could probably add alternative polyadenilation of mRNA precursors, which seems to be Arthur Hunt’s very interesting main field of research.
This is a recent review:
Alternative polyadenylation of mRNA precursors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483950/
And this is probably the most recent paper published by our kind contributor about that:
Noncanonical Alternative Polyadenylation Contributes to Gene Regulation in Response to Hypoxia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502444/
As I said, we never know enough! 🙂
But, in the end, the final question always remains:
Quis custodiet ipsos custodes? (Giovenale)
Who Watches the Watchmen? (Alan Moore)
IOWs, what supraregulates epigenetics? 🙂
ET at #248 (and all interested):
“The one thing we have overlooked is the fact that both splicing and editing require knowledge– meaning they just don’t happen. There has to be knowledge of what to splice and edit- on how to splice and edit- etc”
Great point.
For example, while I was discussing the psaA trans-splicing here, I have wondered many times about the folowing:
How can any system, evolved or not, keep trace of where the different parts are written? Or at least of what the different parts are?
Because that seems a basic requirement to recognize them and to reconstruct the fragmented gene.
Now, in this case we have 4 parts: the three exons with their flanking fragments of the intron, and the tscA gene. They are probably even degenerate: the tscA RNA certainly needs processing before joining the rest.
That reminds me a little of hard disk fragmentation, in a sense! You can write a file fragmenting it in many parts. But you certainly need some record of where the parts are, and of what they are.
Now, the point is that the fragmentation and degeneration of the components of the psaA gene are usually attributed to “rearrangements of organelle genomes”. IOWs, they should be just unlucky events randomly caused by other DNA rearrangements.
One argument in favour of the random origin of the fragmentation could be the simple fact that in similar organisms the same gene is not fragmented.
But if the fragmentation is due to some deleterious random event, why should there be any trace of it? Of the nature and location of the fragments?
Maybe the location is not important, after all. Trans-splicing occurs on pre-mRNAs, and the location of the gene could not be important.
But certainly, the RNA fragments must be recognized, and there must be some trace of how to process and reunite them.
As the gene is a fundamental one, it seems that the rescuing information should have existed before the fragmentation event, or just have been created immediately after the event itself.
Indeed, the fragmentation events cannot realistically be imagined as gradual. It probably rather happened suddenly, as the result of some major DNA rearrangement.
And the organism cannot reasonably avoid strong negative selection, if the gene does not work.
I think that’s the reason why neo-darwinists recur to the bizarre idea of Constructive Neutral Evolution to make some sense of it: the information was certainly there before the event, kindly provided by random neutral events! 🙂
But, if you read carefully the description of what CNE should be, for example here:
http://onlinelibrary.wiley.com.....9/abstract
As you can see, the idea seems to be that “mutations”, maybe not too severe, can be balanced by some existing structure, and that the complexity is built “gradually”.
But there is nothing gradual in the fragmentation of a gene in 4 different parts!
How can any pre-existing structure be “ready” to assist some gene if it is randomly fragmented?
The idea itself is really beyond my wildest imagination!
gpuccio @253:
The plot thickens…
Does this relate (somehow) to your concept of biological “procedures”?
Do we have to wait until next year to read a new comment from professor Arthur Hunt?
Dionisio:
“Does this relate (somehow) to your concept of biological “procedures”?”
Yes, definitely!
“Do we have to wait until next year to read a new comment from professor Arthur Hunt?”
Don’t be impatient. Next year is not so far away! 🙂
gpuccio,
That’s right, this year is practically over.
Let’s wait and see…
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?
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:
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,
Yes, that’s a valid explanation within the neo-Darwinian “anyway, whatever (somehow)” paradigm.
🙂
We haven’t heard from professor Arthur Hunt since last year.
🙂
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:
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):
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:
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,
It seems to me that Arthur Hunt misinterpreted the following sentence from the OP:
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:
Translation: you don’t know what is at the nucleus (heart) of the spliceosome, so you didn’t mention it.
Translation: You could not “clearly identify the essential nucleus of molecules”, right? Well, I did it for you: a self-splicing intron.
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 all
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…)
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,
Perhaps you have experienced otherwise, but I have learned that materialists, without exception, always “succeed” in misunderstanding my arguments.
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,
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-647217
@268:
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…
Any news from professor Hunt yet?
🙂
@268:
That’s related to the OP.
However, curiously professor Hunt’s comments brought up a topic that led to this interesting analysis conclusion:
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:
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:
“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:
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:
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”:
First, an important recognition of the role of mobile elements (ME):
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:
With reference 156 being, among others, the often execrated Mattick!
The roles of mobile elements are many and important (I could not agree more!):
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,
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?
gpuccio,
Perhaps this paper is more recent:
https://uncommondescent.com/evolution/self-organization-new-james-shapiro-paper-on-the-read-write-genome/#comment-647462
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
Emphasis mine.
In what sense “non random”?
From section 7, where all the answers should be:
OK, it is “syntactically organized”.
7.4:
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.
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! 🙂
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. 🙂
@277:
Well, we should know by now: co-option! 🙂
Well, we should know by now: quantum physics! 🙂
@278:
A real treasure trove (of plain nonsense)! 🙂
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? 🙂
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 @282,
Interesting comment about the possible reasons behind Dr. Shapiro’s buttering his bread on both sides. 🙂
Thanks.
ET @282,
Your comment seems to thicken the plot. 🙂
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.
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!
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! 🙂
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.
gpuccio @285:
Agree completely.
I like science, specially biology, which is becoming the queen of science, heavily relying on other branches of science: mathematics, physics, chemistry. Modern biology is closely associated with information technology, cybernetics, control systems.
The fact that the big data problem in biology is turning more serious than in physics confirms the enormous complexity of the biological systems and testifies about the beauty of modern biology.
Unfortunately, many folks out there prefer to waste time on political fights, instead of engaging in polite scientific discussion, like you do here.
gpuccio @286:
Apparently after a quick look I rushed to the wrong conclusion and incorrectly placed the two websites in the same category. Thanks for the correction.
gpuccio @287:
They seem to be alone in the middle of the battlefield, hence they are strongly criticized by both contending sides.
The neo-Darwinian folks go beyond criticism and practically call the third way folks ‘defectors’ and ‘traitors’ in their own terms. That’s not polite at all.
Perhaps that’s the price the third way folks have to pay for buttering their bread on both sides? 🙂
Upright BiPed @288:
All they do is claim ‘natural’ design, ‘natural’ engineering, but their former colleagues in the neo-Darwinian party don’t forgive them for having used such forbidden words as ‘design’ even if it’s sugarcoated with the adjective ‘natural’ in front.
They third way folks crossed the demarcation line and now are being shot at by the neo-Darwinian border patrols.
They either recant their newly adopted ideas and go back to where they were before or change the term ‘natural’ in front of ‘design’ to ‘intelligent’ and join the ID group.
There’s no other side in the battlefield.
Dionisio:
“There’s no other side in the battlefield.”
That’s absolutely correct: no other game in town.
The fight is between RV + NS and design. Nothing else makes any sense.
So, as long as the third way people go on stating that RV + NS can’t do it, they are really arguing in favour of design. Even if they don’t like it! 🙂
Arthur Hunt (and all interested):
Here is a very recent update on the molecular functions of the spliceosome:
The Spliceosome: A Protein-Directed Metalloribozyme
http://www.sciencedirect.com/s.....via%3Dihub
Regarding irreducible complexity, the authors find a very interesting sub-core of the spliceosome which remains remarkably constant throughout the whole spliceosomal cycle:
Emphasis mine.
Arthur Hunt (and all interested):
From the same paper quoted at #294, a very interesting conclusion, absolutely pertinent to our discussion:
Emphasis mine.
Arthur Hunt (and all interested):
This is interesting and pertinent too:
Intron specificity in pre-mRNA splicing.
https://link.springer.com/article/10.1007%2Fs00294-017-0802-8
Paywall.
Arthur Hunt (and all interested):
But neo-darwinists, as we very well know, are not easily discouraged! 🙂
Here is, for example, a very recent just-so story about the evolution of our spliceosome, with some interesting connotations, even in the abstract:
Domestication of self-splicing introns during eukaryogenesis: the rise of the complex spliceosomal machinery.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709842/
Emphasis mine.
No comment! 🙂
@294, 295:
Journal of Molecular Biology
Volume 429, Issue 17,
18 August 2017, Pages 2640-2653
Very interesting paper.
Timely catch!
@297:
Wow! Another interesting paper! Nice catch! Fishing season is on! 🙂
Any news from professor Arthur Hunt yet?
GP at 295.
Boom
The spliceosomal proteins PPIH and PRPF4 exhibit bi-partite binding
https://www.researchgate.net/profile/Tara_Davis/publication/319986193_The_spliceosomal_proteins_PPIH_and_PRPF4_exhibit_bi-partite_binding/links/5a135513aca27217b5a2f32f/The-spliceosomal-proteins-PPIH-and-PRPF4-exhibit-bi-partite-binding.pdf
Upright BiPed @301:
🙂 🙂 🙂
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
…….……. GP @294
…….……. GP @295
…….……. GP @296
…….……. GP @297
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…)
Professor Arthur Hunt posted his last comment in this discussion @164 last December 26, 2017.
Since then gpuccio has addressed to him 17 comments with very insightful explanations.
Perhaps professor Hunt is getting ready to respond to gpuccio?
We look forward to reading his next comments.
@294:
“The rigid protein components include the bulk of the central spliceosomal protein Prp8”
Did we read about this protein Prp8 somewhere else in this thread?
🙂
@295:
“…the overall structure and operational principles of the spliceosome are markedly different from those of the group II introns…”
“…the catalytic activity of the spliceosome, but not of the group II intron, is directed by the protein components.”
🙂
@295:
“The placement and conformation of the RNA elements in the spliceosome are determined in large part by surrounding protein components.”
🙂
@295:
“RNA elements account for more than half of the total molecular mass in the bacterial or mammalian ribosome, but less than 10% in the human spliceosome.”
🙂
@295:
“the spliceosome is a unique protein-directed metalloribozyme.”
🙂
gpuccio,
In the OP figure #2 Prp24 is shown in the center.
Prp3, Prp31, Prp4 are listed under U4/U6 snRNP.
Prp8, Prp6, Prp28 are listed under U5 snRNP.
Then you wrote:
How did you single out Prp8?
Did you look at the other Prp* proteins mentioned above too?
Thanks.
OP brief summary:
Dionisio:
“How did you single out Prp8?”
I sorted out Prp8 essentially because it was the longest protein, it had no sequence homologues in prokaryotes and it was extremely conserved in eukaryotes.
Yes, I looked at most other proteins in my list too, and I could see that, while those features were common to most of them, Prp8 was certainly the one which best exhibited them.
While I went on deepening my understanding of the details of the spliceosome, I also realized that there were a lot of structural and functional reasons to consider Prp8 as the key protein in the spliceosome.
So, this is IMO a very good demonstration that following the tracks of functional information by the methodology I use is a very good and effective way to detect extremely objective functional features! 🙂
@313:
That makes sense. Thanks.
lncRNA involved in alternate splicing?
The known -not the unknown- clearly points to complex functionally specified informational complexity
@315 correction:
lncRNA involved in intron splicing?
Dionisio (and all interested):
Again about Prp8 and its really extraordinary sequence conservation.
I have compared Prp8 with another well known protein, the beta chain of hemoglobin (HBB). This is a small globular protein (147 AAs in humans) with a very important function. However, its sequence-function relationship is not extremely strict, and the protein is known to undergo some important neutral variation in long evolutionary times.
So, I have taken HBB and Prp8 and compared their evolutionary history by blasting the two proteins in Danio rerio (a bony fish) and in humans, and computing the KaKs for both couples of proteins.
Comparing a bony fish with humans gives us an evolutionary time of something less than 400 million years, the assumed time of the fish-tetrapods split, which is a good time frame to evaluate KaKs.
Here are the results. First, the blasts:
HBB (human vs Danio Rerio, 147 AAs):
172 bits
76 identities (51%)
106 positives (71%)
bits per aminoacid: 1.170068
Prp8 (human vs Danio Rerio, 2335 AAs):
4786 bits
2286 identities (98%)
2319 positives (98%)
bits per aminoacid: 2.049679
Now, look at the big difference between these two proteins.
HBB is certainly conserved, but in about 390 million years its sequence retains “only” 51% identities, while Prp8 retains 98% of its sequence.
The difference in bitscore is tremendous (4786 vs 172), but of course it is also due to the difference in length.
But if we use the bits per aminoacid metrics, which corrects for length, the difference is still amazing:
2.049679 vs 1.170068
IOWs the functional specificity, or density, is double in Prp8 if compared to HBB!
Now let’s go to the KaKs ratio.
I will remind here, for the convenience of all, that Ka is the number of nonsynonymous substitutions per non-synonymous site (IOWs, those substitutions which change the encoded aminoacid), while Ks is the number of synonymous substitutions per synonymous site (IOWs, those substitutions which do not change the encoded aminoacid), in the same period.
Here is the simple Wikipedia page:
https://en.wikipedia.org/wiki/Ka/Ks_ratio
from which I quote:
“The Ka/Ks ratio is used to infer the direction and magnitude of natural selection acting on protein coding genes. A ratio greater than 1 implies positive or Darwinian selection (driving change); less than 1 implies purifying or stabilizing selection (acting against change); and a ratio of exactly 1 indicates neutral (i.e. no) selection”
and
“The Ka/Ks ratio is a more powerful test of the neutral model of evolution than many others available in population genetics as it requires fewer assumptions.”
So, just to simplify:
Forget the values above 1 (they are very rarely seen).
Values near to 1 indicate neutral variation in the whole sequence (non synonymous mutations happen at the same rate as synonymous mutations)
Values significantly lower than 1 indicate negative (purifying) selection: non synonymous mutations are antagonized by negative selection.
In proteins where the sequence is conserved, we expect values lower than 1.
To compute the KaKs I have used the R package seqinR, and the function kaks.
So, let’s see:
HBB (Danio rerio vs human):
Ka = 0.3799238
Ks = 1.399608
Ka/Ks = 0.2714501
This value is well below 1, so we can say that HBB has been under negative (purifying) selection in the last 390 million years.
But let’s go to Prp8:
Prp8 (Danio rerio vs human):
Ka = 0.0139506
Ks = 1.482462
Ka/Ks = 0.009410427
Two important points:
a) The rate of synonymous substitutions (Ks) is absolutely comparable in the two proteins:
HBB vs Prp8
1.399608 vs 1.482462
This means that the rate of neutral variation is rather constant. This is, as I have said many times, the best proof of molecular common descent.
b) The rate of non synonymous substitutions (Ka), instead, is strikingly different. In both proteins, indeed, it is lower than the Ks, but in Prp8 it is much lower (almost 30 times lower!):
HBB vs Prp8
0.3799238 vs 0.0139506
As a consequence, the Ka/Ks ratio is almost 30 times lower in Prp8:
HBB vs Prp8
0.2714501 vs 0.009410427
IOWs, both proteins are under purifying selection, but the purifying selection, as measured by the low Ka/Ks, is almost 30 times stronger in Prp8!
So, there can be no doubts about the functional specificity of the Prp8 sequence!
gpuccio,
Interesting analysis. Thanks.
What common molecule did the proteins HBB and Prp8 come from?
Dionisio:
“What common molecule did the proteins HBB and Prp8 come from?”
No common molecule, as far as I can see.
They belong to different protein superfamilies, and they have nothing in common.
If we blast one against the other (the human forms), the bitscore is 16.9, with an E value of 2.0.
I would like to clarify one thing.
When I say that we have strong evidence of molecular common descent, I mean that the protein homologues derive physically through common descent.
IOWs, Human Prp8 derives with physical continuity for the Prp8 of the common ancestor of fish and tetrapods, to remain with my previous example.
That is the only way we can explain the value of the Ks between the two proteins: neutral variation has acted on the protein, in each of the two lineages, after the split, in a way that is grossly proportional to time.
Remember the values of Ka, Ks and Ka/Ks between human Prp8 and Fish Prp8 (390 million years split):
Prp8 (Danio rerio vs human):
Ka = 0.0139506
Ks = 1.482462
Ka/Ks = 0.009410427
Now, if we compute the same values between human Prp8 and mouse Prp8 (less than 100 million years split) we have:
Prp8 (Mouse vs human):
Ka = 0.000870346
Ks = 0.4489751
Ka/Ks = 0.001938517
Here, again, the Ka/Ks ratio is extremely low, because the Ka is greatly lower than the Ks.
Hower, both Ka and Ks are much lower than the values we found in Danio rerio.
Ka: 0.000870346 vs 0.0139506
Ks: 0.4489751 vs 1.482462
And if we look in particular to the two Ks values, which are influenced only by neutral variation, the ratio (fish-human / mouse/human) is:
3.30188
This corresponds rather well (considering the many approximations in evolutionary times and intrinsic variance of biological systems) to the ratio between the two approximate split times:
390 / 80 = 4.875
The important point is that such gross proportionality is retained throughout all groups of organisms and all time spans.
For example, if we compute the Ks for human and chimp Prp8, the result is:
Ks (chimp – humans): 0.01565742
Again, the ratio:
fish-human Ks / chimp-human Ks
1.482462/0.01565742 = 65
is comparable to the ratio between the approximate split times:
390 / 6 = 94.68112
There is always this correspondence, extremely significant even is not precise, between evolutionary times and Ks values, in each pairwise confrontation.
I am aware of no possible explanation for that pattern, other than neutral variation acting on homologues that are physically transmitted throughout evolutionary times.
That’s what I call molecular common descent.
But when a new protein superfamily appears, there is no reason to believe that it derives from some other sequence ancestor. It could, if the engineering starts from some existing protein sequence, but if the engineering is so relevant that no sequence or structure similarity remains detectable (as it is the case for different superfamilies), we can have no proof of that derivation.
Of course, a new sequence could also be engineered from non coding sequences, and therefore have no derivation from other protein sequences at all.
For Prp8, we have seen that there are no sequence homologies in prokaryotes, but many believe that there are vague structure similarities with reverse transcriptases, and that therefore the molecule could distantly derive from some such sequence.
As I have said, that is possible (but certainly not certain), but it is not interesting at all from the point of view of functional complexity, because the working sequence of Prp8 has nothing in common with reverse transcriptases except for vague structure similarities, and Prp8 is definitely not a reverse transcriptase.
The huge functional sequence that is conserved almost entirely from the first eukaryotes to humans has practically nothing in common with the sequence of reverse transcriptases, and is a true sequence novelty that appears in eukaryotes.
https://www.inverse.com/article/40032-evolution-of-life-on-earth-complex-metabolic-chemistry
Hi origin of life solved again
es58:
This is, I suppose, one example of the “metabolism first” approach.
These guys are hopeless, but at least they have understood that metabolism is a severe necessity for any form of life, which is certainly true. So they try the impossible to pursue that way.
The tone of the “non scientific” article, however, is really funny:
“Scientists think about 3.8 billion years ago, a cocktail of organic compounds managed to come together in some way to create the first life. We know it was primitive and dumb, but still — it was life!”
This is, instead, the more serious abstract of the paper itself, for those who could be interested:
gpuccio,
My question @318 was dumb, but you graciously still managed to answer it @319 with a very clarifying (as usual) explanation and with sufficient technical details (also as usual) that even I can understand it.
Thanks.
Enjoying reading this series!
Introns, the Spliceosome, all the other guidance mechanmisms in place for splicing are fascinating in regards to information processing, decision trees or branching.
Was going to post previously in relation to Direct Access Methods – known as Random Access Method in past.
What is Rule of Random Access Method?
It is Not Random.
It’s directed. Highly regulated addressable assets for storage and retrieval.
Great stuff at 295-… on down 🙂
I suspect Introns are excellent case for Design principles.
Found a bit more on paper you highlighted at #296…
http://emboj.embopress.org/content/37/1/89
It’s at Research Gate as well.
Found this PDF by these authors here:
Sde2 is an intron-specific pre-mRNA splicing regulator activated by ubiquitin-like processing>
From the abstract:
Activated for guided, specific splicing.
Mutations could cause inefficiency or failure?
“Sde2-C is an intron-specific pre-mRNA splicing factor”
Fascinating regulatory functions. Wish I had more time to join in and catch up.
Look forward to reading Hunt’s opinions on all of your postings Gpuccio. And where he migh have agreements or disagreements.
DATG:
Thank you for your inputs. I will look at them with great interest! 🙂
You are always welcome to the discussion. 🙂
before I forget, was going to post the other day on “Fragmented” and narrative of fragmented genes, etc., as
degradation of original DNA.
Maybe, certainly it makes since from a bottom-up, series of random mutations and unguided happenstance…
from your previous post on “spoiled kid hypothesis…” and “evolutionary ratchet”
What if instead of assumptions of blind process and degeneracy, we ask why this might be intentionally dispersed in relation to information as a definitional, rules based allocation of resources? For specific placement and retrieval purposes?
Another words, what might we be missing in terms of specific processing needs and organizational structure, as well as coordination? Design often times has trade offs, but with specific intent of cost/benefit analysis. What may look chaotic, degenerate, may be a different use for exceptions.
Just thinking outside the box.
DATCG @323:
That’s interesting what you’ve found.
I look forward to reading gpuccio’s comments on your posts.
DATCG @324:
I’m looking forward to reading professor Hunt’s future comments on the pile of comments gpuccio has addressed to him.
The distinguished professor is probably very busy with his many academic activities, but let’s hope he’ll find some time to come back and present his counterarguments to the detailed explanations gpuccio wrote in this thread.
DATCG @326:
Maybe, certainly it makes since from a bottom-up
sense?
DATCG:
The “Direct Access Method” idea is very interesting. I have thought many times that this complex issue of introns, fragmentation of information, and so on strongly reminds information access problems in hardware and software.
In comment 254 I wrote:
“That reminds me a little of hard disk fragmentation, in a sense! You can write a file fragmenting it in many parts. But you certainly need some record of where the parts are, and of what they are.”
The whole issue of spliceosomal introns in eukaryotes is a deep mystery. I think we still miss some important aspects of the whole matter.
Interestingly, as you very correctly suggest, while the spliceosome itself is a rather universal and flexible machine/system, a lot of extra components add to its function, making it specific for particular introns or group of introns, maybe providing also further support to regulation through alternative splicing. The Sde2 system, described in the paper you linked, is a very good example of that.
It’s particularly fascinating that such a mechanism (the Sde2 involvement in the spliceosome for the specific splicing of certain pre-mRNAs) is connected to the ubiquitin-specific proteases system, a regulation network which involves practically all cellular systems.
Another interesting aspect is that the proteins involved (Sde2, UBP5, UBP15), while universally present in eukaryotes, change a lot in the course of natural history. In that sense, they are very different from Prp8 and other spliceosomal proteins.
UBP15, for example, a 981 AAs long protein in humans, has very low homology scores in saccharomices species, the best hit being just 391 bits.
This low conservation in regulatory proteins is, IMO, almost always a sign of functional differentiation, rather than low functional specificity (like in the case of HBB).
So we apparently have a scenario of a rather conserved spliceosome which acts a an universal machine, whose behaviour in different cases and in different species is finely regulated by lots of accessory factors, probably very specific for the different scenarios and the different species, and therefore much less conserved and highly differentiated.
DATCG @326:
“What if instead of assumptions of blind process and degeneracy, we ask why this might be intentionally dispersed in relation to information as a definitional, rules based allocation of resources? For specific placement and retrieval purposes?”
intriguing concept… hmm…
the plot thickens…
🙂
@330:
“The whole issue of spliceosomal introns in eukaryotes is a deep mystery. I think we still miss some important aspects of the whole matter.”
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
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…….……. GP @231
…….……. GP @242
…….……. GP @253 **
…….……. GP @254 **
…….……. GP @263
…….……. GP @268
…….……. GP @294
…….……. GP @295
…….……. GP @296
…….……. GP @297
…….……. GP @313 **
…….……. GP @317 **
…….……. GP @319 **
…….……. GP @330 **
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
(**) related to the main discussion, but not addressed to professor A. Hunt directly
(to be continued…)
gpuccio @330:
RE: DATCG @323
reminds of modularity, systems drivers for specific devices, OOP/OOD object classes, etc.
are you saying that those concepts in Computer Science were defined long before the universities were created?
🙂
Dionisio:
“are you saying that those concepts in Computer Science were defined long before the universities were created?”
So it seems! 🙂
gpuccio @330:
“So we apparently have a scenario of a rather conserved spliceosome which acts a an universal machine, whose behaviour in different cases and in different species is finely regulated by lots of accessory factors, probably very specific for the different scenarios and the different species, and therefore much less conserved and highly differentiated.”
OK, this is a very delicate issue you’ve raised here.
Let me explain:
My former boss, the director of software development for y employer, came up with a killer idea that catapulted the product they developed to the top of the line in its niche industry. His idea, which was wisely based on his knowledge and experience in the given engineering design field, but also -very importantly- based on his numerous consultations with other engineers in the field.
What was his idea? Well, basically what you just described in the mouthful statement quoted above. That’s basically it. That was the game changer at that time.
But now you tell me that his brilliant idea was thought of long before him?
Next time I talk to him I’ll mention this… I’ll let you know his reaction.
After looking at the amazing biological systems, computer-based systems out there look like Lego Duplo for toddlers.
🙂
gpuccio @330:
“It’s particularly fascinating that such a mechanism (the Sde2 involvement in the spliceosome for the specific splicing of certain pre-mRNAs) is connected to the ubiquitin-specific proteases system, a regulation network which involves practically all cellular systems.”
a recent ubiquitin-related paper is referenced here:
https://uncommondescent.com/evolution/rethinking-biology-what-role-does-physical-structure-play-in-the-development-of-cells/#comment-647913
Dionisio:
Very interesting paper.
With 500-1000 E3 ligases which provide the necessary specificity, the ubiquitin system could well be one of the most complex regulatory systems in biology! 🙂
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 @119 **
…….……. 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
…….……. GP @294
…….……. GP @295
…….……. GP @296
…….……. GP @297
…….……. GP @313 **
…….……. GP @317 **
…….……. GP @319 **
…….……. GP @330 **
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
(**) related to the main discussion, but not addressed to professor A. Hunt directly
(to be continued…)
Any news from professor Arthur Hunt yet?
🙂
Was this the last time we heard from the professor?
164 December 26, 2017 at 8:10 pm
That’s a few days short of 3 weeks ago. Not that long yet. We still can wait…
But maybe in the meantime, we could start refreshing our memory on some terminology of what used to be considered the Royal Game before computers took over it.
Text quoted from
https://www.chess.com/learn-how-to-play-chess
I think we’re seeing an obvious checkmate in this case, but that’s just my uneducated opinion. What do y’all think it is?
BTW, was Paolo Boi (c. 1575) the greatest chess player from Sicily ?
🙂
Dionisio:
I don’t know why Arthur Hunt has not provided his announced argument. However, as you say, we still can wait.
I like intellectual confrontation, and in a sense it can be compared to a fight, or to a chess game. But there is one important difference. In intellectual confrontation, it’s not really important who wins or loses. In a sense, nobody wins or loses.
What is really important is the discussion itself, the ideas that surface, the sincere approach to truth. That is true, IMO, for any serious discussion, and in a particular way for scientific discussions.
So, when good ideas are expressed, and truth remains the true aim of the discussion, maybe even of the fight, I do believe that everyone wins.
I hope that in this discussion a few good ideas have emerged. 🙂
In the meantime, I would say that many interesting aspects of the spliceosome, and of some related structures, have been touched in some detail. That’s good.
My personal impression is that, in the end, the strong premise which is the title itself of the OP has been convincingly argued for:
The spliceosome is a molecular machine that defies any non-design explanation.
But, of course, that’s just my opinion.
And, as you said, we still can wait… 🙂
Dionisio:
“BTW, was Paolo Boi (c. 1575) the greatest chess player from Sicily ?”
You definitely know more about Sicily than I do! 🙂
gpuccio @342,
Agree.
What matters at the end of a serious discussion is how much additional light has been shed on the big picture. That’s why a prerequisite for serious discussions is that all discussants are interested in finding the truth about the discussed topic. I don’t think that condition is always met.
In this particular thread I think several interesting related issues have been presented in your excellent OP and in the many follow up comments you and other folks have posted. Thus some of us -specially I- have learned very interesting things.
Biology is turning more fantastic every day. I don’t know how far it can get at this pace, but it’s definitely fascinating, at least to me.
I appreciate the effort you make and the time you take to research so thoroughly the topics you explain so well here.
@343:
There were other famous Italian chess players before the world championships started, but they were not from your neighborhood. I think they were from Napoli (or is it Naple?).
Something I still don’t know is how well they cook in the restaurants by the littoral in Palermo.
The only way to find that out is going there personally.
I might start planning a trip there after professor Hunt posts his next comment here.
🙂
gpuccio,
Someone said that chess used to be a Royal Game before the computers took over it. Now the mystery behind it is practically gone.
gpuccio @342:
Actually, I think it has been strengthened. At least until professor Hunt presents his strong counterargument. Then things might change.
Let’s wait and see…
🙂
https://www.google.com/amp/www.newsweek.com/life-solar-system-likely-exists-and-more-common-we-think-780229%3famp=1#ampshare=http://www.newsweek.com/life-solar-system-likely-exists-and-more-common-we-think-780229. More life for free?
But they do mention the discovery on meteors of homochiralic amino acids which itself seems unlikely
es58,
is that all? then poof! really?
I prefer Disney’s Cinderella’s fairytale, because it makes more sense:
a pumpkin converted to an elegant carriage, mice turned into beautiful horses, and a grasshopper hired as the official “cochero”.
🙂
BTW, this thread is about the spliceosome, which is an amazing machinery, according to gpuccio’s OP and follow-up comments.
Some of us are looking forward with much anticipation to reading professor Hunt’s next comment, where he supposedly should present the breakthrough counterargument that will finally punch a hole in gpuccio’s presentation.
#330 Gpuccio,
Yes 🙂 More I hope to add later. Not enough time tonight.
Came across a video and thought you guys might enjoy. Particularly first line by narrator.
Hope to see Hunt respond to your series of post Gpuccio.
Structure of a Spliceosome: Molecular Framework for Understanding Pre-mRNA Splicing…
https://www.youtube.com/watch?v=JnBf3tq_aXY
I remember Harvard geneticist George Church pointing out to ID scientist and enthusiast to research the Ribosome.
A series of quotes from Harvard geneticist George Church…
Yes, good dialogue, debate, discuss, gain insights.
Those are nice sentiments and welcome. And addition of Hunt’s comments here are most welcome. Bridge building is good. Sharpening of each side and insights through debate is healthy and wise, certainly for learning.
I wonder what Church thinks about the Spliceosome 🙂
Why did he encourage ID to focus on ribosome? What does he see in it as Design worthy defense?
Similar to Splceosome? 🙂
ps Thankful for Edit function, I’ve corrected several spelling mistakes in post-edit process.
DATCG:
Very good thoughts! Very good video too.
Church seems to be a very interesting personality. The idea of building bridges is the only real solution to the stupid polarization of ideological scientism vs ID. Unfortunately, not many people seem really interested in building those bridges, on both sides, even if of course with different responsibilities.
The ribosome is of course another wonderful molecular machine. More ancient, of course, and that makes probably the discussion more difficult.
Here is a rather funny “just so story” from Wikipedia about its “evolution”:
“The ribosome may have first originated in an RNA world, appearing as a self-replicating complex that only later evolved the ability to synthesize proteins when amino acids began to appear.[47] Studies suggest that ancient ribosomes constructed solely of rRNA could have developed the ability to synthesize peptide bonds.[48][49][50] In addition, evidence strongly points to ancient ribosomes as self-replicating complexes, where the rRNA in the ribosomes had informational, structural, and catalytic purposes because it could have coded for tRNAs and proteins needed for ribosomal self-replication.[51] Hypothetical cellular organisms with self-replicating RNA but without DNA are called ribocytes (or ribocells).[52][53]
As amino acids gradually appeared in the RNA world under prebiotic conditions,[54][55] their interactions with catalytic RNA would increase both the range and efficiency of function of catalytic RNA molecules.[47] Thus, the driving force for the evolution of the ribosome from an ancient self-replicating machine into its current form as a translational machine may have been the selective pressure to incorporate proteins into the ribosome’s self-replicating mechanisms, so as to increase its capacity for self-replication.”
Just for fun. No comment! 🙂
DATCG:
“ps Thankful for Edit function, I’ve corrected several spelling mistakes in post-edit process.”
The ribosome would agree!
DATCG @350:
Very interesting video indeed.
Thanks.
https://www.youtube.com/embed/JnBf3tq_aXY
#352 and Gpuccio knocks it out of the paaark! 😉 Great paper, thanks!
#351 well said! Like Church, Venter’s work. Sadly, wonder what kind of heat Church takes simply for offering an olive branch? What is awful is scientist losing positions in the past, even recently.
What is fascinating after all these years is the “appearance of design” is not going away. It’s growing stronger in terms of language appropriation.
The paper you reference on Quality Control systems for Protein Synthesis is a case in point.
In their conclusion…
When Design appropriate words are only words you can use to describe overall system behavior at this level, the game is over so-to-speak.
How else would you describe the system in place? Other than Quality Control? That’s precisely what it is. A highly regulated QC system. That error checks, is triggered to action and termination if required of production.
QC can have several different levels in engineering or coded systems.
Simplifying:
1) non-threatening – function remains,
2) partial error – degradation – but allowable
3) danger – abort switch activated – production stopped
In order to recognize these different levels, error checking mechanisms must match triggers – be cognizant – monitor the processing at different check points, up until final post processing procedures. Proceed or Terminate.
Error checking cannot happen randomly.
To early in a process, misses errors entirely. To late, may not miss it, but damage done cannot be rectified in time.
Quality Control is time dependent. Imagine at these speeds of production and size.
Different situational outcomes are required for each type of error triggered. Code check depends on narrowed targets or milestones in any phase or post-production stage. Whether it’s materials processing or programmed routines.
Because even error checks need specific routine calls to complete decision outcome and alert other processes to restart or continue, exit, etc.
So what about RNA Modification? In the Spliceosome. Is there Post-processing there too? 🙂
Correction last line #354, on RNA modification, post-transcription process.
and…
Error checking, Quality Control through out. From pre-mRNA onward before being fully processed and passed through Nuclear Pore Complexes on way to cytoplasm.
DATCG:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912188/
Moreover, while I have focused my attention especially on Prp8, there are many other important protagonists in the spliceosome. Brr2 is certainly a very good example:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224448/
By the way, if we look at these two very big proteins in humans:
Prp8: 2335 AAs
Brr2: 2136 AAs
which have such a fundamental role in the U5 subunit of the spliceosome, at the core of the spliceosome itself, and which so strongly interact one with the other, we could be tempted to believe that they are in some way also sequence related, betraying some similar functional information and derivation.
Well, they are not.
If we blast human Prp8 vs human Brr2, here is what we get:
Just three minimal and non-significant homologies:
Score: 22.7 bits. Total score: 64.3 bits
E-values: 0.74, 2.4, 2.7
IOWs, we have two completely different, independent functional sequences, which strictly cooperate to make the spliceosome work.
Is that irreducible complexity? You bet!
And is Brr2 highly conserved from single celled eukaryotes to humans? You bet! In the range of 2700 bits! (see Fig. 4 in the OP).
And has Brr2 some sequence homology in prokaryotes? Yes, but rather low: 311 bits in archaea.
And is Brr2 highly functionally constrained? You bet!
ExAC values are 8.00 standard deviations for missense mutations, and 1.00 for probability of Loss of Function. Almost like Prp8!
DATCG @354-356
Very interesting commentary. Thanks.
Also, nice work provoking gpuccio to write more on that interesting topic here.
🙂
Any news on professor Arthur Hunt yet?
🙂
#357 Gpuccio,
Thanks! will review those papers.
#354 correction, “error checking cannot happen randomly”
is intended to be in regards to specific location(s).
Typically checkpoints happen at key intervals, not randomly. At known areas of transmission, data manipulation and translation. Before and after.
I’m typing to fast without doing my on checking 🙂
Or course error checking at location points can be random, in fact encouraged for reasons of efficiency.
As I’ve done many times based on a set of instruction sets to limit numbers, but maintain overall quality control.
So constraints of error checking or recognition triggers can fluctuate as required. For example hardening a site for anti-virus.
The amount of checks may increase along with information triggers. And key component checks may expand, increasing larger load and longer run times.
Gpuccio,
In searching error processing, noticed you’d originally posted video I shared. LOL, so yes, it’s a good one!
I’d read through your post, but not watched video. My apologies!
Gpuccio, on 1st paper linked…
“Because regulation of this process determines the timing and location that a particular protein isoform is produced, changes of alternative splicing patterns have the potential to modulate many cellular activities. Consequently, pre-mRNA splicing must occur with a high degree of specificity and fidelity to ensure the appropriate expression of functional mRNAs.”
Timing and location matter. How does a hardware system of blunders, mutations finalize correct timing and location before meltdown? Without built-in communication sensors and systems?
Even if one assumes no error processing?
Which opens you to a runaway RNA train. I’d like to know how these issues are overcome by mutational events and “junk” dna.
gpuccio @357:
Well, at least until professor Arthur Hunt comes back here and punches a hole in that ID concept.
BTW, don’t the neo-Darwinian / modern synthesis / extended synthesis folks have someone else who could debate gpuccio here?
Is professor Arthur Hunt their only ammunition?
Are they really that weak?
🙂
Ok, if professor Hunt can’t come back, then what about the distinguished Canadian biochemistry professor at the U of T?
I promise not to ask any dishonest questions with tricky words.
gpuccio doesn’t need help to defend his solid presentation.
Actually, gpuccio’s presentation doesn’t need to be defended. The neo-Darwinian folks lack arguments anyway.
Well, let’s wait and see.
🙂
DATCG is doing a nice work keeping the serious discussion going.
Dionisio:
“Is professor Arthur Hunt their only ammunition?”
Of course, we cannot force people to take part in the discussion. We can only thank them if they do that! 🙂
Dionisio:
“DATCG is doing a nice work keeping the serious discussion going.”
Yes. 🙂
Exactly a month ago, December 21, 2017, gpuccio started this discussion thread with an excellent OP.
The first comment was posted right away. That very first day, less than 10 hours after the thread had started, the distinguished professor Arthur Hunt posted a challenging comment @25. Does this mean that UD posts are being closely watched by some academics out there? Maybe. 🙂
The last time we heard from the distinguished professor was in his comment posted @164 December 26, 2017.
We still look forward to reading his expected counterargument.
In the meantime gpuccio’s OP title remains valid and unchallenged.
Gpuccio,
I would appreciate your comment on this:
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-649630
Thanks.
Dionisio:
I would simply say that Hox genes, and more in general TFs, are a good example of how partially conserved genes can retain some essential functions over a wide spectrum of organisms, and at the same time gain new and specific functions through changes in sequence, or in regulatory elements.
That confirms the idea, which I have many times expressed, that proteins are much more complex than we usually think. While final effector proteins may use their functional information in a rather compact way, to implement some very specific biochemical function, regulatory proteins, like TFs, or more in general master regulators, are much more flexible, and they are used as functional modules with multiple, often apparently unrelated roles.
That’s why their natural history often exhibits a frustrating mixture of sequence conservation and divergence, which seems to correspond to a similarly frustrating mixure of conserved and divergent functions.
The complexity, and functional fine tuning, of the whole scenario is simply amazing.
gpuccio,
Excellent statement to summarily conclude your comment @370:
“The complexity, and functional fine tuning, of the whole scenario is simply amazing.”
Thanks.
The occurrence of spliceosomal introns in eukaryotic genomes is highly diverse and ranges from few introns in an organism to multiple introns per gene. Introns vary with respect to their lengths, strengths of splicing signals, and position in resident genes. Higher intronic density and diversity in genetically complex organisms relies on increased efficiency and accuracy of spliceosomes for pre-mRNA splicing. Since intron diversity is critical for functions in RNA stability, regulation of gene expression and alternative splicing, RNA-binding proteins, spliceosomal regulatory factors and post-translational modifications of splicing factors ought to make the splicing process intron-specific. We recently reported function and regulation of a ubiquitin fold harboring splicing regulator, Sde2, which following activation by ubiquitin-specific proteases facilitates excision of selected introns from a subset of multi-intronic genes in Schizosaccharomyces pombe (Thakran et al. EMBO J, https://doi.org/10.15252/embj.201796751, 2017). By reviewing our findings with understandings of intron functions and regulated splicing processes, we propose possible functions and mechanism of intron-specific pre-mRNA splicing and suggest that this process is crucial to highlight importance of introns in eukaryotic genomes.
Mishra, Shravan Kumar & Thakran, Poonam. (2018). Intron specificity in pre-mRNA splicing. Current Genetics. . 10.1007/s00294-017-0802-8.
https://link.springer.com/article/10.1007%2Fs00294-017-0802-8
Introns Protect Eukaryotic Genomes from Transcription-Associated Genetic Instability
http://www.sciencedirect.com/s.....6517304963
Dionisio @373
thanks for paper on more Intron functions.
This goes back to my @230 post on Intron Functions, “… suspect more will be found.”
Looking for functional design elements in Intronic regions can be rewarded.
Design elements can simply be a switch, an enhancer or silencer, etc.
From paper you posted…
DATCG,
Your comments are very appreciated.
BTW, tomorrow it will be one month since the last time professor Arthur Hunt posted a comment in this thread, where he started a discussion with gpuccio the very first day gpuccio’s OP appeared.
We don’t know why the professor hasn’t come back to defend his previous comments, which seemed intended to punch a hole in gpuccio’s ID presentation.
The professor’s conspicuous absence could make one suspect he ran out of valid arguments and decided to quit, after seeing that his comments couldn’t make even a shallow dent in gpuccio’s presentation, not even a scratch.
Perhaps it would have been better to publicly recognize the strength of gpuccio’s presentation and rejoice in the light that was shed on the discussed topic for everybody’s benefit.
Dionisio,
Maybe, but I doubt Hunt thinks he lacks valid arguments. In his comments he’s confident and comfortable with his statements.
I’m am waiting for his expansion on his ideas and evidence from #164. And hopeful he responds to Gpuccio’s detailed rebuttals and information.
I’ve gathered and read different papers on historical evolutionary pathways to the spliceosome. Much of what is said is vague and lacks detail. So I’m hoping he can shed more light on the subject.
Where does he disagree in detail with Gpuccio on evolution of the Spliceosome? And Irreducible Complexity?
Quoting a paper Gpuccio referenced in comment #295…
“RNA elements account for more than half of the total molecular mass in the bacterial or mammalian ribosome, but less than 10% in the human spliceosome. For this and all other reasons discussed previously, the spliceosome is a unique protein-directed metalloribozyme.”
1) RNA elements account for half of total molecular mass in bacterial or mammalian ribosome
2) RNA elements account for less than 10% in human spliceosome.
3) The spliceosome is cited as a “unique” Protein-Directed metalloribozme(you highlighted at #310).
Is the spliceosome “unique” according to authors of that paper? Does Hunt disagree with paper’s conclusion?
If so, why?
I hope he can add more specific detail where he disagrees with Gpuccio’s responses and and and expand on his own offerings in #164.
At least Hunt’s recognizing ID’s hypothesis of Design and challenging Irreducible Complexity on it’s own merit instead of dismissing with ridicule. He’s engaged and I’d like
to see more engagement like this.
Precisely the kind of dialogue needing to take place if science is to progress. This is healthy for scientific pursuits in molecular genetics.
I think Design provides a more natural heuristic thought process of research and discovery. Based upon a systems approach.
Where as unguided thought processes gave us “junk” DNA and limited thinking.
I hope Hunt responds. Lets enjoy robust disagreement and discussion. Gpuccio has done his part. Awaiting Hunt’s comments.
Or, for that matter, if Hunt does not respond, any other neo-Darwinist supporter that supports Hunt’s conclusions.
DATCG,
Agree. Thanks.
DATCG:
I absolutely agree with you! 🙂
DATCG,
Encouraging timely news!
gpuccio has invited a distinguished scientist, who just recently coauthored a very interesting paper in a very prestigious peer-reviewed journal, to join the serious discussion that the distinguished professor Arthur Hunt started with gpuccio here but unfortunately hasn’t continued since a month ago today.
Here’s the link to gpuccio’s invitation:
https://uncommondescent.com/intellectual-freedom/re-seversky-a-lot-of-this-reads-like-complaining-because-science-isnt-coming-up-with-observations-and-theories-that-you-like/#comment-650106
This would be like the replacement of the starting pitcher in baseball. 🙂
DATCG @376:
“I doubt Hunt thinks he lacks valid arguments. In his comments he’s confident and comfortable with his statements.”
Then what else can explain his conspicuous absence from here for a whole month?
We don’t know. We hope it’s all well with him.
But it seems like he quit after the temperature in the discussion went up when gpuccio posted his solid responses.
At least that’s the impression left. But that could be a misperception.
Obviously, appearances can be deceiving.
Let’s wait and see…
Gpuccio, Dionisio I see you’ve made Bob aware of this post.
Good, maybe he will join in 🙂
Dionisio, re: reasons for Hunt’s not posting since Dec 26th?
Not sure, there may be another reason. I’ll wait to see if he post or not. Hopefully he will continue. Could be he’s extremely busy. I’ll give him that benefit for now. He may be preparing a longer commentary in response to Gpuccio as well.
We shall see.
DATCG and Dionisio:
I really think that he must do as he thinks better, there is no obligation to post here. And of course maybe he is only too busy.
The only problem for me is… I am a very curious person!
So, I go on wondering what are the subunits of the complex he is studying that defy the logic used here! 🙂
OK, I must probably work on my character flaws… 🙂
gpuccio,
curiosity is bothering me too
gpuccio,
Apparently another kind of curiosity is bothering other people out there too…
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650304
Would you mind to comment on some of the proteins mentioned in the referenced paper?
Thanks.
gpuccio, DATCG,
what do you think of this?
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650344
Dionisio, will give it a look. Has Bob commented on it?
Dionisio:
Very interesting review about cytokinesis. I will try to look deeper into it. 🙂
Ok, let’s try to keep the readers entertained while waiting for professor Hunt (or a substitute?) to come back and try to say something about the avalanche of solid arguments gpuccio has posted hee in this thread.
Off topic-
Lite “nerdy” fun starting @300 here:
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650409
gpuccio, DATCG,
The link posted @385 points to posts @289-291 in the linked thread.
Just the abstracts are available. Do they give a hint of the current situation in the neo-Darwinian party?
DATCG @386,
Bob? Do you mean Bob O’H, the scientist associated with Norwegian and German institutions, who just coauthored (along with other 114 scientists) an interesting paper in the peer-review Science journal?
Is he interested in this heavy-duty kind of science discussion gpuccio leads here?
gpuccio @387:
“Very interesting review about cytokinesis.”
Yes, the link @384 points to post #279 in another thread, where an interesting paper on cytokinesis is referenced.
I thought your interesting comments on involved proteins is always very appreciated here.
Thanks.
DATCG, you’re welcome to look @391 and comment too.
However, by now I think I have entangled the links so badly that it’s hard to figure out what to look at.
Sorry. 🙂
Dionisio:
I am reading the paper linked at #385. I will come back about it. 🙂
gpuccio,
Thank you.
I’m interested in reading your comments on both, the cytokinesis proteins linked @384 and the one linked @385 about the state of affairs in the modern synthesis/neo-Darwinian theory. If I have to chose one between the two, I prefer the former (cytokinesis).
But either way you decide to go, take your time, no rush. As long as you can tell us something sooner than a month from now, you’ll do much better than other folks who have taken longer to reappear in this thread. 🙂
gpuccio,
Just heard of the ‘replisome’?
Any comments on those proteins?
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650529
Thanks.
gpuccio,
this reminds me of something you have mentioned:
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650607
Dionisio at #396:
You bet! The evidence for the role of transposable elements as design tools that shape functional information in genomes is constantly growing. 🙂
Ok, now I see why that paper rang a bell to my ear.
Thanks
gpuccio,
Have you seen this paper?
It’s not new.
Notice some familiar terminology used in the paper.
https://uncommondescent.com/evolution/this-parody-of-evo-devo-makes-it-sound-a-lot-like-id/#comment-650617
Sorry, I’ve been dumping many paper references here.
Just wanted to share it.
Dionisio:
About the paper at #399.
Yes, interesting terminology and definitely an attempt to approach evolution from the point of view of functional information.
But, apart from that, a real disappointment in the end: just a summary of neo-darwinist stereotypes without any real meaning.
That’s what happens when you exclude in advance the only true explanation: design.
Well, well, nothing from Arthur Hunt. Just a fly by, a mention to use google, a mention to look at certain aspects of splicing and evolution.
But no defense or even offense.
I will state my opinion now why he has not posted. If I’m wrong, please Arthur Hunt let us know.
My thought is he has not commented again in fear of giving any legitimacy to Gpuccio’s well researched post and follow-up.
There’s a few ways Darwinist, neo-Darwinist, unguided macro-evolutionist rebut Design.
1) They insult and try to malign it
2) They bluff with large amounts of papers
3) They reference vague material on the subject of macro-evolutionary paths of ancient, unknown ancestors
4) They refuse to engage at all or out of fear do not do so
5) They engage legitimately on the subject
6) They engage the person and subject on scientific
publication, but refuse to allow the person the same
privilege as happened to Dr. Michael Behe
#5 I think Hunt began with a good discussion, legitimate
insights and opposition to Gpuccio that make for good
debate on the topic
#4 But, at this late date, with no rebuttal or answers to Gpuccio’s detailed commentary I suspect Arthur Hunt
may have received heat for being here at all. And
dropped out due to fear of fellow scientist and zealots on the other side of the debate.
They simply do not want a real discussion and debate take
place on facts, observances, science and data.
If so, that is sad. Because science does not progress without robust disagreement, discussion and debate.
Insights are gained by instructive disagreements.
So many here abuse Design Theorist and Scientist by saying
they are not published or science is not discussed here.
But we all know that is not true.
The truth is when science is discussed, none of these false accusers show up to discuss on a good post like this one by Gpuccio. They make excuses.
It’s hypocrisy.
I was truly hoping to gain some insight, even if critical of Design by Hunt.
Maybe he will return one day and share his views. Maybe he was afraid to take it on, or worse was told not to do so. We may never know.
But by not commenting and not challenging Gpuccio, he leads himself open to criticism. Fairly so.
DATCG:
Thank you for your comments. In general, I can agree with what you say. But of course I must remain neutral about Arthur Hunt specifically, not knowing the true reasons for his “disappearance”.
I must say that I have thought some of the things that you have thought, but I want to remain open-minded, and I try not to judge when I am not sure of what truly happened.
As you have already seen, having been the first to comment on my new OP, I try to go on with my approach to biological design. The interest and support of those who, like you, share some of my views are the best encouragement that I can receive. 🙂
Alternative Splicing of Transcription Factors
Imbriano, Carol & Molinari, Susanna. (2018).
Genes in Muscle Physiology and Pathology. Genes. 9. 107. 10.3390/genes9020107.
http://www.mdpi.com/2073-4425/9/2/107/pdf
A new paper discussing Introns and Alternative Splicing, Introns roles and some new revelations…
Transient N-6-Methyladenosine Transcriptome Sequencing Reveals a Regulatory Role of m6A in Splicing Efficiency
Awesome stuff on selective splicing and processing!
Dionisio! there you are!?! 🙂
Gpuccio@403, you are always generous to your detractors.
And Arthur was on topic and kind as well. It’s one reason why I was hoping for more of his insights and input on the discussion.