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Author
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Topic: Cytosine Deamination from Both Sides
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Mike Gene
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Member # 149
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posted 01. February 2003 15:24
INTRODUCTION
I have previously illustrated that the effects of cytosine deamination, expressed through the conventional genetic code, appear to bias mutational consequences by increasing a protein's hydrophobicity and predisposition to form secondary structures. [1] This form of bias may have been designed into life's matrix to facilitate evolution. [2]
Up to this point, however, I have only explored the consequence of deamination in the coding strand of DNA (the strand of the double helix that is not transcribed, thus shares the same coding sequence of the RNA product formed by using the transcribed DNA strand). Yet, since C is normally paired with G, C-T transitions on either strand of any gene will also result in G-A transitions of the opposite strand. In other words, the effects of cytosine deamination on a gene with the sequence CGATGTAACGTAGTA will experience transitions at both the C and G sites.
SUMMARY
The Increasing Hydrophobicity Effect as mediated by C->T transitions is not significantly altered by factoring in the G->A transitions that would be coupled (Figure 1). Most of the amino acid substitutions brought on line by including G->A transitions are either conserved or of modest effect (Figure 1 and 2). The only exception is to include glycine in the amino acid pool that is targeted, meaning that the net effect of CG->TA transitions is to target both of the strongest helix breakers for possible removal, thus further facilitating the formation of new secondary structure (Figure 3). Basically, what this means is that the effects of CT mutations elicit the IHE and increase the predisposition to form secondary structure, while the only thing the incorporation of the GA mutations seem to add is an increased predisposition to form alpha helices and eliminate turns.
The most fascinating aspect of these relationships is their dependence on the double-stranded genome. The consequences of CT mutations predominate in this dynamic and are also enhanced by the transactions that take place because a double-stranded DNA molecule is transcribed by a large protein complex. And it is also quite remarkable that proline codons are C-rich, while glycine codons are G-rich, meaning that when both strands are factored, both of "the strong helix breakers" are targeted for removal [4]. It is quite a coincidence that the two residues that have long been noticed to share this feature [5] just happen to be subject to the most common form of base substitution.
For the rest, see http://www.idthink.net/biot/deam2/index.html
[ 26. February 2003, 14:36: Message edited by: Moderator ]
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Moderator
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posted 19. March 2003 14:31
I'd like to see discussion on this topic. Any takers?
[ 19. March 2003, 14:32: Message edited by: Moderator ]
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Rex Kerr
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posted 19. March 2003 18:19
This is interesting, but cytosine deamination is only one of many possible ways of generating a point mutation. If you compare human genomes looking for single base-pair changes and use that to estimate recent mutation rates in humans, you find that the rates of C/G->A/T are 1.7 times more frequent than A/T->C/G--a fairly small bias. Further still, when you compare human and chimp genomes, you find only a bias of 1.4. This suggests that there may be a bias towards keeping the A/T->G/C substitutions, which is backwards from what this model might predict. (Source for information: Webster et al., "Compositional Evolution of Noncoding DNA in the Human and Chimpanzee Genomes", Molecular Biology and Evolution v20pp278-286.)
Given these data, is there really much support for the speculation that cytosine deamination is particularly favorable for evolution? It is a reasonable-sounding hypothesis, but biolgical evidence has a way of overturning apparently reasonable hypotheses.
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Art
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posted 19. March 2003 22:27
Rex,
It's already been pointed out that oxidative changes contribute more to the occurrence of point mutation that C deamination. I'm not sure Mike really cares about this - rather, I think he would prefer that we brainstorm given the initial premise, even if incorrect.
Such as: if C deamination is such a driving force in shaping genomes, then why haven't organellar genomes reached the expected low C content that would obviate the need for C->U editing in RNA? Not only do these two processes seem redundant in the context of this idea, the "need" for editing actually seems to contradict the initial premise (that C deamination is the predominant mode of point mutation). In the context of Mike's ideas, can this contradiction be reconciled? (I don't have any answers, but this would seem to be fertile ground for a few ideas.)
For what it's worth, once again, one excerpt from the review article on mutational mechanisms that is relevant (from Maki, Ann. Rev. Genet. 36, 279-303, 2002):
quote:
“The nature of native replication errors caused solely by action of the replicative apparatus has been extensively characterized, whereas less is known about spontaneous DNA lesion that potentially induces spontaneous mutations (24). Active oxygen species are produced in aerobically growing cells and attack DNA to produce a wide range of lesions. An estimated 3000–5000 oxidative DNA lesions/cell/generation are produced in cells of E. coli under normal aerobic growth conditions (78). Free nucleotides are attacked more efficiently by oxygen radicals than DNA, and in a number of different species, oxidized nucleotides are produced in the cellular nucleotide pool. Among them, 8-oxodGTP (58) and 2-OHdATP (37) possess extraordinarily strong mutagenicity. Considering their high production rate, these mutagenic compounds are potentially the most powerful source of spontaneous mutations. Methylation and hydrolytic decomposition of DNA such as depurination and cytosine deamination cause a variety of endogenous DNA lesions (24). However, the spontaneous frequency of these events is estimated to be much lower than that for the oxidation of DNA.”
[ 19. March 2003, 22:29: Message edited by: Art ]
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Nel
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posted 06. April 2003 20:40
Mike,
I am enjoying reading your essays on cytosine deamination.
I've been thinking of what might be other ID predictions that one can make that may be related to this hypothesis. Protein structure may be strongly influenced by the boundaries of the coding sequence. On the C-terminus, you can find TAA-ochre, a TAG-amber, or a TGA-opal, stop codons themselves seem to resist C-T/G-A transitions. Transition of both opal and amber gives ochre which is very resistant to C-T/G-A transition. All of this suggests that C-T transition help stop gene exansion from the C-terminus. When you look at the N-terminus you'll find an ATG that would sometimes transition t ATA. A prediction from this might be at the N-terminus genes will expand as methionine start codons become isoleucines. With this hypothesis in hand one can look at prokaryotes and predict that C-terminal domains would be older than N-terminal domains.
[ 05. July 2003, 21:36: Message edited by: Nelson-Alonso ]
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Rex Kerr
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posted 07. April 2003 00:40
Nelson, that's an interesting insight. However, changing Met->Ile doesn't in any way move a start site earlier. You still need an earlier Met to start on, and if one is there, you'll typically start there rather than at the later one. So it doesn't actually work, but it's an interesting thing to consider.
Also, note that stop codons can be cytosine-deaminated into but not out of. This would tend to suggest that cytosine deamination would have a bias towards truncations.
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Nel
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posted 07. April 2003 14:43
Rex wrote:
quote:
However, changing Met->Ile doesn't in any way move a start site earlier. You still need an earlier Met to start on, and if one is there, you'll typically start there rather than at the later one. So it doesn't actually work, but it's an interesting thing to consider.
I don't see how this would not make it work. What you are talking about is if the Met is the first one on the transcript, then of course the Met-Ile would not be able to initiate translation. However, a prokaryote not only initiates translation internally but also undergoes polycistronic transcription. Thus, a Met-Ile will cause the sequence to grow at its 5' end.
You also write:
quote:
Also, note that stop codons can be cytosine-deaminated into but not out of. This would tend to suggest that cytosine deamination would have a bias towards truncations.
This is irrelevant. You can make new stop codons but when you do, it might be resistant to being cytosine deaminated.
[ 07. April 2003, 15:18: Message edited by: Nelson_Alonso ]
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Nel
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posted 07. April 2003 15:32
Art wrote:
quote:
It's already been pointed out that oxidative changes contribute more to the occurrence of point mutation that C deamination.
I actually have more to say about this issue, but I also think that this is a good area for research (finding out of c-deamination is a dominant form of mutation). But I just wanted to offer some balance here. There are many studies that also show that c deamination is dominant. From Mike's former reply:
quote:
high rates of nucleotide substitution and C-->T transitions, usually found for pseudogenes - Yokoyama
et al.
The most frequently occurring base substitution mutation observed in aerobic organisms is a GC->AT transition. This substitution is also the most abundant genetic change induced as a consequence of oxidative DNA damage. - Kreutzer and Essigmann
In most forward mutation assays, insertion and/or deletion mutations or C-to-T substitutions dominate the spectrum. For example, in one study of spontaneous Rif r mutants (17) G _ C-to-A _ T transitions comprised 72% of the obtained mutations. In a study of lacI d mutations (19), 29% of the mutations were insertions or deletions, and of the base substitution mutations 47% were G _ C-to-A _ T changes. Such dominance of frame-shifting mutations and C-to-T mutations in the spectra means other base substitutions such as G _ C to T_ A are rarely seen. - Klapacz Bhagwat (your citation)
And as I mention above, several pseudogene and SNP analyses support this position (which is not merely "my" claim). And as I mentioned also, the data from Klapacz and Bhagwat showed the frequency of C-T transitions was 100-1000-fold higher than all these non-CT mutations.
[ 07. April 2003, 15:34: Message edited by: Nelson_Alonso ]
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Mike Gene
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posted 10. April 2003 00:28
Sorry for no replies lately. I've been entirely focused on the war. I've always said that ID is an intellectual hobby of mine, thus when something I become deeply passionate about comes up, ID got put to the side for the moment. I hope to return to ID thinking in a short time. Thanks.
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Rex Kerr
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posted 10. April 2003 08:06
Polycistronic genes still read 5'-3', and read through later Met codons rather than start at them. Also, stop codons do cause truncations, so I'm not sure what you mean by "irrelevant".
I've never seen a SNP or mutational study that shows anything like a thousandfold excess of C->T mutations. Can you quote the methods of the work that purported to show this? I don't know what they were doing.
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Nel
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posted 10. April 2003 13:08
Again Rex, polycistronic transcription allows internal translation, which supports what I said with regard to prokaryotes, since what happens with Met-Ile will be independant of what is at the start site. Therefore, Met-Ile will cause the sequence to grow at its 5' end. And again, the point about "stop codons can be cytosine-deaminated into but not out of" is irrelevant, this just suggests that you can make stop codons, but it might be resistant to C-T.
You wrote:
quote:
I've never seen a SNP or mutational study that shows anything like a thousandfold excess of C->T mutations. Can you quote the methods of the work that purported to show this? I don't know what they were doing.
Mike was referring to the reference by Bhagwat et. al.Transcription-dependent increase in multiple classes of base substitution mutations in Escherichia coli with respect to the 100-1000-fold higher comment.
[ 10. April 2003, 13:09: Message edited by: Nelson_Alonso ]
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Rex Kerr
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posted 10. April 2003 20:05
Nelson, thanks for the more complete reference to the paper. If you read it, you'll find that they did their experiments in the ung mutant background, which can't repair cytosine deamination! So, of course, the mutations that can't be repaired are observed much more frequently than those that can be.
As to the rest of your post, it would be nice if you could recognize when you are under-informed about a topic and either do some reading or at least not repeat the same erronious claims.
First, you claim genes can grow at the 5' end, and that this is interesting. I say that the same process can make them shrink at the 3' end, and you claim it is "irrelevant". Please explain why. I'd think that changing the N-terminus and C-terminus of a protein were both interesting effects, if true.
More importantly, you seem to misunderstand prokaryotic translation. Here's some excerpts from Molecular Genetics of Bacteria by Snyder and Champness--although any good genetics book should give similar information:
quote:
Translation Initiation
The process of initiating the synthesis of a new polypeptide chain is very different from the process of translation once it is under way. [...]
TRANSLATION INITIATION REGIONS
In the chain of thousands of nucleotides that make up an mRNA, the ribosome must bind and initiate translation at the correct site . . . mRNA have sequences called translation initiation regions (TIRs) that flag the correct first codon for the ribosome. In spite of extensive research it is still not possible to predict with 100% accuracy whether a sequence is a TIR. However, some general features of TIRs are known.
Initiation Codon
All TIRs have an initiation codon, which codes for a definable amino acid. The three bases in these codons are usually AUG or GUG [or others, rarely] . . . . Regardless of which amino acids these sequences call for in the genetic code (Table 2.1), if they are initiation codons, they encode methionine (actually formylmethionine (see below)) as the N-terminal amino acid. After translation, this methionine is usually cut off [...]
Shine-Dalgarno Sequence
Given that the initiation codons code for amino acids other than methionine when internal to a coding region, the presence of one codon is clearly not enough to define a translational initiation region. [...]
Many bacterial genes have 5 to 10 nucleotides on the 5' side (upstream) of the initiation codon that define a ribosome binding site. These sequences, named the Shine-Dalgarno sequence after the two scientists who first noticed them, are complementary to short sequences within certain regions of the 16S RNA. [Figure shows AGGAGGU complementing UCCUCCA in the 16S rRNA.] [...]
Polycistronic mRNA
In bacteria and archaea, the same mRNA can encode more than one polypeptide. Such mRNAs, called polycistronic mRNAs must have more than one TIR to allow simultaneous translation of more than one sequence o fthe mRNA. . . . Even if the two coding regions overlap, the two polypeptides on an mRNA can be translated independently by different ribosomes.
There is a figure showing an example much like:
code:
----[RBS--AUG]-----------------[UAA].........[RBS---AUG]-------------[UAG]
TIR #1 stop spacer TIR #2 stop
RBS = ribosome binding site
spacer is -1 to 40 bp.
Now, I hope from all this it is obvious that simply deleting an AUG somewhere isn't going to give you a longer 5' end--you need to move the RBS also.
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Nel
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posted 12. April 2003 13:00
Rex,
With respect to the Bhagwat paper, I havn't read it yet, so I don't know if you are misinterepting it. I only quoted that portion of Mike's response to show that Art's statement about Mike "not caring" if cytosine deamination is predominant was false. And that there are many instances in the literature where it does show that cytosine deamination may be predominant. Which is why I said "I have a lot more to say about it". I'll return in future postings to discuss that if I get the time.
With respect to "repeating myself", in your second reply, you simply talked about polycistronic genes still reading from the 5'-3' end. That wasn't what I was pointing to, thus the need to "repeat" myself.
You say:
quote:
First, you claim genes can grow at the 5' end, and that this is interesting. I say that the same process can make them shrink at the 3' end, and you claim it is "irrelevant". Please explain why. I'd think that changing the N-terminus and C-terminus of a protein were both interesting effects, if true.
Simply because I'm interested in what may be happening at the C-terminus. If it's true what you say, I am not sure of the significance. Which is why I said it was irrelevant. What matters is that, at the C-terminus, expansion is defended against due to C-T transitions. This may be related to Mike's hypothesis, and I am brainstorming about this. How the possibility of shrinkage at the C-terminus is relevant to this is unclear. Get it?
My point about methionine start codons, was because at the C-terminus, because of C-T transitions, they are being kept from expanding, but at the N-terminus, they might expand, giving us a test to work with. Now you seem to be disagreeing with me that something will cause expansion at the N-terminus. My only point here was to make sure that my hypothesis had a testable prediction to work with in that we can see c-terminus older than n-terminus, if the idea has any teeth.
You write:
quote:
"simply deleting an AUG somewhere isn't going to give you a longer 5' end you need to move the RBS also "
Speaking of being under-informed, there are prokaryotes that lack an RBS,
Moll et al J Bacteriol 183:3499-3505,
and still undergo translation, or don't have normal ones and therefore pass directly from one gene to another. Thus my prediction may be testable with these cases.
[ 16. May 2003, 15:03: Message edited by: Nelson_Alonso ]
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Mike Gene
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posted 13. April 2003 18:07
Since I haven't given ID any thought over the last few months, let's see if I can get up to speed first by painting the larger picture surrounding this topic. Afterwards, I can get to the specific comments.
The hypothesis that I propose is that cytosine deamination may have played an important role in the front-loading of evolution. This hypothesis is a direct response to Poole et al.'s claim that "Any engineer would have replaced cytosine." This claim appeared in the peer-reviewed literature and the hypothesis I raise seriously calls such an assertion into question.
Because of my speculations that center around ID and how it might serve to front-load evolution, I noticed a relationship between the effects of cytosine deamination and the genetic code [1]. And as far as I have been able to tell, no one else has noted this relationship, despite the fact amino acid properties, the genetic code, and cytosine deamination have been known for decades. The relationship I noted has allowed me to propose testable hypotheses regarding the front-loading of evolution [1]. Furthermore, there are studies that demonstrate the IHE could very well apply to evolution [2].
What's more, this hypothesis has been developing a modest track record of success in overcoming criticisms. One criticism was that while cytosine deamination might be channeled to facilitate protein evolution, it has no "function" regarding RNA biochemistry. Yet as I noted, "It is also worth commenting on the apparent conceptual tie between the effects of cytosine deamination on protein and RNA structure/function. In both cases, the most common base substitution appears to have significant functional potential, as both hydrophobic amino acids and uracil seem to make the greatest impact of protein and RNA structure, respectively. It's as if an engineer is trying to get the "most bang from your buck" when it comes to utilizing a nitrogenous base poised to change." [2] Another criticism was that the IHE was not significant if we factored mutations on both strands of the DNA. Yet the essay linked to above addresses this criticism (see the summary I listed above).
I should also make it clear that I have never proposed cytosine deamination as the major driving force behind all of evolution. In fact, I have made it clear that I view this process working in conjunction with the originally designed state, such that it helped to unpack buried designs. I specifically spelled it out as such:
quote:
From a design perspective, this model of evolution need not exert its effects in a ubiquitous fashion. Instead, perhaps only key events in life's evolution were significantly helped by this "directed evolution." However, there is an unfortunate caveat worth mentioning. The ability for C-T transition to unmask front-loaded states may have long ceased to exist. Such a dynamic may have been crucial to some early events in evolution, yet given these states may have dissipated (the proximal objectives were reached), current mutations may no longer reflect any detectable design bias . In such a case, the current predominance of C-T transitions (involved in some disease states) may simply be a vestige of design.
Finally, it is important to recall the brainstorming lessons that were previously discussed [3], as they don't suddenly cease to apply.
Anyway, I'll try to get to specific comments in the next few days. In the meantime, it would help to read where I have covered some of this material before [4,5].
1. http://idthink.net/biot/deam/index.html
2. http://idthink.net/biot/ihe/index.html
3. http://www.iscid.org/boards/ubb-get_topic-f-6-t-000282.html
4. http://www.iscid.org/boards/ubb-get_topic-f-6-t-000269.html
5. http://www.iscid.org/boards/ubb-get_topic-f-6-t-000170.html
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Mike Gene
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posted 17. April 2003 23:35
ID thinking is still pretty rusty, but let me try to fire it up.
It's important to understand the actual claims behind my hypothesis. I have not proposed that cytosine deamination is, and always has been, the driving force behind genomic evolution. It is an ID hypothesis, attempting to account for the inclusion of the base cytosine in the genetic material. As such, it is a hypothesis centered around the design on the original biotic material and the genetic code. It is a hypothesis further linked to the hypothesis of front-loading, whereby the code was designed to extract buried designs in the original sequences. And I envision more to the story than simple deamination and selection. As I hinted before:
quote:
That's an interesting thought. Are you suggesting that C-T transitions would be one way to take a position "off-line" such that is escapes the regulatory circuit involving C-methylation (and its associated effects)? As I mentioned before, I have not got around to pondering the genomic opportunities provided by such biased mutations.
One thing that is interesting from the paper you mention is the observation that transcription through CpG islands is associated with increased methylation rates. Transitions involving Me-C result in the production of thymine directly, which allows cells to escape the ung-directed error correction. Couple this to the fact that deamination is associated with transcription also and the opportunity exists for accelerated sequence evolution of expressed genes.
and
quote:
It may have been even more sophisticated than this. Using thymidine in DNA would allow cells to escape Ung surveillance simply by methylating the cytosines. This is because the deamination product of Me-C is thymine, not uracil. Thus, a cell could theoretically regulate ung and cytosine methylase activities, making it possible to target increased hydrophobicity to specific regions of a protein.
And there's more to it than this.
Yet the sound approach, to start with, would be to consider whether early events in evolution (such as the evolution of multicellularity) were impacted by these biological dynamics. I thus raised a testable hypothesis concerning that addresses this.
The data Rex mentions don't really address the hypothesis I raised. First, we would have to assume this mechanism of front-loading was intended to play out 3.5 billion years after the original design, such that today, buried designs still exist. I don't find this intuitively plausible. In other words, the intended designing effects mediated by cytosine deamination may have largely played out already and are largely controlled by efficient proof-reading mechanisms. What would seem more interesting to me is to consider the sequences that distinguish human from chimp and determine if C-T transitions are represented more often than we would expect by chance.
As for the relationship between cytosine deamination and genomic evolution, there are a couple of interesting papers worth reading that suggest under certain conditions, the predominance of cytosine deamination will assert itself.
First, there is the interesting read by Jean R. Lobry, which I link to in my original essay:
quote:
Do you know what is at the top of this mountain? It is the origin of replication of the B. burgdorferi chromosome that, incidentally, has just been experimentally mapped. As a consequence, when you are climbing the mountain you are reading the lagging strand for replication and when you are going down the mountain you are reading the leading strand for replication. What is usually found, but not always if you remember Synechocystis, is that the leading strand is enriched in keto (G or T) bases and that the lagging strand is enriched in amino (A or C) bases. Interestingly, these biases have been reported for both eubacteria and archaea, mitochondria, chloroplasts, viruses and plasmids, but not for eukaryotes up to now. In B. burgdorferi the biases are so important that they affect the amino acid content of proteins and you can guess if a protein was encoded on the leading or the lagging strand solely from its amino acid content............. This fundamental asymmetry of replication may explain the universality of the observed systematic biases in base composition; these are at least compatible with the hypothesis. The protection against cytosine deamination may differ between species and explain the variability in intensity of biases.
Then, there is the paper by Fryxell and Zuckerkandl (Cytosine Deamination Plays a Primary Role in the Evolution of Mammalian Isochores. Molecular Biology and Evolution 17:1371-1383 (2000)):
quote:
DNA melting is rate-limiting for cytosine deamination, from which we infer that the rate of cytosine deamination should decline twofold for each 10% increase in GC content. Analysis of human DNA sequence data confirms that this is the case for 5-methylcytosine. Several lines of evidence further confirm that it is also the case for unmethylated cytosine and that cytosine deamination causes the majority of all C" src="/math/rarr.gif" border=0T and G" src="/math/rarr.gif" border=0A transitions in mammals. Thus, cytosine deamination and DNA base composition each affect the other, forming a positive feedback loop that facilitates divergent genetic drift to high or low GC content. Because a 10°C increase in temperature in vitro increases the rate of cytosine deamination 5.7-fold, cytosine deamination must be highly dependent on body temperature, which is consistent with the dramatic differences between the isochores of warm-blooded versus cold-blooded vertebrates. Because this process involves both DNA melting and positive feedback, it would be expected to spread progressively (in evolutionary time) down the length of the chromosome, which is consistent with the large size of isochores in modern mammals.
As for the relative occurrence of point mutations, I did read the review paper Art brought up but was disappointed to find that it did not devote much attention to this particular issue, nor provide extensive citations that would be helpful. As an outsider, it looks like the issue is still open, as other scientists have asserted cytosine deamination to be predominant. But more on this issue later.
As for RNA editing, I really don't see the problem here. I provided an example whereby RNA editing exploits cytosine deamination to demonstrate the reality of the IHE. It's a proof-of-principle demonstration that adds plausibility to my hypothesis. The advantage to RNA editing, rather than mutating the genome, takes us to the soft-wiring ability of RNA (to be discussed later) and the fact that RNA editing often allows a cell to expresses two variants of a gene at the same time. In such cases, no single example of a C-T transition at the genomic level may be beneficial. But through massive editing, multiple C-T events in multiple genes might impart significant protein re-design such that a benefit it imparted. In fact, in a quasi-IC likeness, the beneficial state might depend on multiple simultaneous mutations in the context where expressed original sequence is likewise maintained.
The most significant thing about Art's critiques is that they clearly highlight that the notion that ID cannot generate a scientific research program has been debunked. Clearly, an ID lab could focus on whether cytosine deamination is indeed the most common form of point mutation. Here is a clear scientific question, of widespread interest, that an ID lab can address (whether the question can be addressed without ID is not relevant). Furthermore, I already mentioned that it would be interesting to characterize the edited gene products and compare them unedited products. What is the functional significance of that editing and does it depend on multiple, simultaneous changes?
Finally, Nelson brings up an interesting hypothesis that is related to something I wrote earlier:
quote:
True, as I did get ahead of myself (on ARN, I noted that I was already working on extensions of the evolution-through-deamination hypothesis). So let me offer a brief preview. Each of the three stop codons (UAG, UGA, and UAA) can be reached by a single cytosine deamination event. If we consider both strands, the CG:UA transitions can reach 7/9 positions. In contrast, the stop codons themselves are not nearly as prone to mutation through deamination (none contain cytosine). This asymmetry suggests that base substitutions are more likely to generate nonsense mutations than chain elongation mutations (not to mention that the codon pool to reach nonsense mutations is larger than the codon pool to reach chain elongation mutations). This makes sense from a front-loading perspective, as premature termination might unleash a subset of domains roughly analogous to Force's DDC hypothesis. This could then set up selective pressure for recombination of domains. Chain-elongators, on the other hand, simply end up translating noise, which is probably less useful from an evolutionary perspective. This thus intersects with error correction and my thesis, where apoB is a good proof-of-concept example. Anyway, I'll expand on this in a latter essay.
If I get the time some time soon, I'll try to expand, as I found another neat little fact that fits into the puzzle. I also try to comment on your hypothesis, Nelson. ![[Wink]](wink.gif)
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