Genes that appear from nowhere — a tutorial

_{Denyse O'Leary

February 21, 2023

Genetics, Intelligent Design}

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A friend notes — about these de novo (from nowhere) genes — that narrator Anne-Ruxandra Carvunis stresses that the genetic patterns she studies don’t fit the evolutionary theory learned “since I was an undergraduate.” The de novo gene literature mirrors that, we are told.

Well, if she has a job story instead of a sob story, eventually, the discrepancies will add up.

Comments

Alan Fox: I'll await your next response; however, in the meantime, this is from the link that you provided:
Further a 1:1 stoichiometric ratio of purine and pyrimidine bases (i.e., A+G=T+C) should exist. This pattern is found in both strands of the DNA. They were discovered by Austrian-born chemist Erwin Chargaff, in the late 1940s.
This is exactly what I said: no preferences exist. There are slight preferences that we now know about (since the 1940'w), but Chargaff's Rules still fundamentally and generally apply. This means that as far as basic biochemistry within the cell, there are no known forces pushing nucleotides in one direction or another, to say nothing of there being a bias of this kind sort of on demand. The mathematics, therefore, are straight forward. That you would point to Chargaff's Rules in this discussion is like telling a college student that "i comes after e except after c." On this blog, the "ivory tower" is left behind, I'm afraid. :)PaV_{March 4, 2023
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PaV, trying to comment on a phone is too much trouble. I'll pick this up tomorrow when I have time and a larger screen.Alan Fox_{March 3, 2023
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PaV
We know that the probability of a particular nucleotide base to find itself in a sequence of such bases is the same, more or less, for all four nucleotide bases.
The Wikipedia article on Chargaff's Rules summarizes much research over the years into the distribution of nucleotide bases in DNA/RNA sequences. It's not just probability, it's a result of physical and chemical properties, critically: the property of pair-bonding.Alan Fox_{March 3, 2023
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Alan Fox: Let's start here:
Only? Your method doesn’t (nor can it) show that. It’s a mathematical model that does not approach reality.
The "islands" I referred to were 'islands of functionality.' The connection between these islands shouldn't, generally speaking, easily happen. We know that mutation and selection can move alleles around in the island they belong to, and even allow them (I would think on extremely rare occasions) to move to another island of functionality. All this means is that the sequence space must be extravagantly large. For human beings in labs, this is difficult. For an All-Powerful God, this is much easier--though the Good Lord "rested" from his "work." I'll leave it at that. As to the mathematical model I used not "approach[ing] reality," we obviously differ here. We know that the probability of a particular nucleotide base to find itself in a sequence of such bases is the same, more or less, for all four nucleotide bases. Hence, back of the envelope calculations give us quite some insight. Sir Fred Hoyle did such a calculation. If the argument is that, "he's not an evolutionary biologist," well, neither is Szostak, whose paper you cited and I looked at. He's a "molecular biologist," just like, if I may add it here, Michael Behe. In Szostak's April 2001 paper, he concludes thusly:
we suggest that functional proteins are sufficiently common in protein sequence space (roughly 1 in 10^11) that they may be discovered by entirely stochastic means, such as presumably operated when proteins were first used by living organisms.
Life can't exist without proteins. And here he's assuming that life does already exist. This is circular reasoning because his thesis is this: since life exists, then protein function can be "discovered by entirely stochastic means," which proves that "entirely stochastic means" can give rise to life. Isn't this logically incoherent? As to the paper itself, I understand the method he employed and why he employed it; however, he ends up on some kind of strange "island" of functionality:
A NetBLAST7 search of the NCBI protein sequence databases shows that the most closely related known protein sequence to the 45 amino acids of the minimal functional sequence of this protein has only a 33% identity. This is not a significant homology for a sequence this short, and did not include any of the four conserved cysteines.
It seems strange that there is hardly any homology at all with anything found in nature. But there was another problem. Unlike ATP-binding that happens in biological systems, this Family B mutated and selected protein, "protein 18-19," seemed to need help for it to bind.
These observations suggested that family B proteins might require a coordinated metal ion to be functional. Elemental analysis by atomic absorption spectroscopy revealed the presence of one equivalent of bound zinc, and no other divalent metals. Incubation of the protein with EDTA results in a concentration-dependent loss of ATP-binding activity. Activity can be restored to protein that has been extensively dialysed in the presence of EDTA by the addition of Zn2+, but not Mg2+, ions.
And a little later:
We suggest that the family B proteins bind to ATP with a folded structure nucleated around, or stabilized by, a Zn2+ ion coordinated to the four invariant cysteines of the CXXC sequences. None of the other three protein families selected in this study contains this zinc binding motif, and no known biological nucleotide-binding domain is a zinc-stabilized structure, although the glucocorticoid receptor contains a similar pair of CXXC sequences and binds to DNA in a zinc-dependent manner.
So the ATP-binding activity of protein 18-19 is brought about in a way that isn't found in nature. No homology, and a binding mechanism that is not found in nature, and a mechanism that relies on a metal ion to fold sufficiently for it to bind to the ATP. So what is it that they've mutated themselves to? If it weren't for nascent blood in the petri dishes, Zn2+ would not have been available and protein 18-19 would not have bound to ATP. The other three sequence lines had a very low level of binding to ATP, even after, IIRC, being mutated and amplified. So, yes, they produced, in random fashion, a sequence that could 'bind' to ATP; however, as far as living cells are concerned, this "protein" must seem like a pile of junk. It feels like something of a stretch to say they really found a "functional protein."PaV_{March 3, 2023
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This is a good place for an insightful assessment
To paraphrase someone much smarter than me. A little bit of science inclineth one to atheism A lot of science inclineth one to God
So true! https://twitter.com/HotHarveyW/status/1557578480912543750jerry_{March 2, 2023
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You only have to ensure that the various islands of probability within the total sequence space are probabilistically far enough away from each other that they effectively don’t mix.
Only? Your method doesn't (nor can it) show that. It's a mathematical model that does not approach reality.Alan Fox_{March 2, 2023
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Yes, I'm aware of "sauce for the goose".Alan Fox_{March 2, 2023
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Oops just noticed messed up blockquote. PaV said:
My answer makes more sense than your question.
I replied: If you are referring to your back-of-envelope calculation, then I’m sorry to tell you it is based on false assumptions. I’ll repeat, density of functionality, and how similar functions can be achieved by different, unrelated sequences, whether exhaustive search is relevant, undermine your model. I'd add that, of course our own statements make sense to us. The skill in communication is to make sense to others. Beware Dunning and Kruger.Alan Fox_{March 2, 2023
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I wasn’t kidding. You asked a silly question.
What question? My answer makes more sense than your question.If you are referring to your back-of-envelope calculation, then I'm sorry to tell you it is based on false assumptions. I'll repeat, density of functionality, and how similar functions can be achieved by different, unrelated sequences, whether exhaustive search is relevant, undermine your model.Alan Fox_{March 2, 2023
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Alan Fox: I wasn't kidding. You asked a silly question. My answer makes more sense than your question.PaV_{February 27, 2023
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Alan Fox: Yes, Hoyle's is an "all-in-one-go" calculation, as it should be: no cytochrome c, then no duplication. If there is nothing but death, that is not "differential" death. This all is so obvious. I can't believe intelligent people can't see this somewhat immediately. A quick look at Szostak's paper, his abstract, shows that he is NOT calculating the 'density' of functional proteins in 'sequence space,' but rather something along the lines of the density of putative functional proteins in "functional protein space": that is, his denominator is not 2^6x10^9, but something like 2^6000. That's 2^10^6 times smaller. This is a mind-boggling huge difference. From the paper you cite:
The frequency of occurrence of functional proteins in random-sequence libraries appears to be similar to that observed for equivalent RNA libraries
Axe does similar work and comes up with numbers that show the frequency is outstandingly small even within the libraries, let alone all of sequence space for the length of the human genome. JVL: There are 3 billion nucleotides in DNA. There are four nucleotides. So, the denominator (i.e., total sequence space for the human genome) is 2^2 x [2^3 x(10^9)]= 2^6x(10^9). JVL:
You’re proposing a lot of possibilities. It would take some time to check them all out. And how would you check them out.
You don't need to "check them all out." You only have to ensure that the various islands of probability within the total sequence space are probabilistically far enough away from each other that they effectively don't mix.PaV_{February 27, 2023
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In the opposite direction, we have Hoyle’s calculation for cytochrome c. How does this form randomly?
I'm guessing Hoyle's is an all-in-one-go calculation like his tornado in a junkyard. Proteins can start as promiscuous and evolve specificity.Alan Fox_{February 27, 2023
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...dwarfs the numerator, which is the total number of known functional sequences in the human genome...
What is at issue is the density of functional proteins in sequence space. This is unknown. Jack Szostak threw a little light on it with their seminal paper and work continues. You might like Andreas Wagner's Arrival of the Fittest for an overview.Alan Fox_{February 27, 2023
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Why would Doug Axe be wrong?
Well, that's a philosopher's question. I can only tell you Axe's (2004) work is badly flawed. I'd sum it as an elegant example of the Texas sharpshooter fallacy.Alan Fox_{February 27, 2023
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As to an approximate figure for infinity, it’s this: infinity minus one.
I'll give you the benefit of the doubt and assume you are joking.Alan Fox_{February 27, 2023
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PaV: how could a designer come up with a design unless he’s aware of the parameters available You're proposing a lot of possibilities. It would take some time to check them all out. And how would you check them out. divide that by the total number of sequences in sequence space for human cells. 2 raised to the six billionth power, which is the divisor Could you explain how you get to 2 raised to the 6 billionth power?JVL_{February 27, 2023
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JVL: Yes, 1 in 22^105. As to your doubts about a designer, how could a designer come up with a design unless he's aware of the parameters available? What makes you think that God lives in time? He's an Infinite Being. Now that's who I think is the Designer, because otherwise I can't see who could have devised biological life with our puny human intelligence.PaV_{February 27, 2023
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Jerry, The quote you include in your last post mention concepts and ideas that Ruth presents in the video. Why would Doug Axe be wrong? He did the experiments--actual experiments, versus notions of proto-genes, whose operation and existence present problems to evolutionary theory. But, I'll take a look.PaV_{February 27, 2023
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Alan Fox: Take the total number of functional sequences we know of, multiply that number by a million, and then divide that by the total number of sequences in sequence space for human cells. 2 raised to the six billionth power, which is the divisor, completely overwhelms and dwarfs the numerator, which is the total number of known functional sequences in the human genome multiplied by a million. In the opposite direction, we have Hoyle's calculation for cytochrome c. How does this form randomly? How can cell life take place, let alone divide, without it? Where did it come from? Either way, the astronomically small probability makes thinking this can be explained by physical forces alone, in my opinion, nothing more than metaphysics. As to functionality and specificity, what you write indicates you don't understand either concept as it's presented by ID advocates. You confuse "particular" modes of functionality and specificity with the more "general" modes of what function and specificity is. As to an approximate figure for infinity, it's this: infinity minus one.PaV_{February 27, 2023
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PaV: a 105 a.a. long protein has the probability of randomly coming about (assuming it won’t be destroyed upon appearance) of 22^ 105. Umm . . . probabilities are between 0 and 1 so I assume you meant something like 1 in 22^105 OR 22^-105. Not that that makes sense anyway since I doubt even your designer has the 'time' to check out all the possible combinations.JVL_{February 27, 2023
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Alan Fox: Can you give me a approximate figure for infinity, then? Which one? :-)JVL_{February 27, 2023
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Here is Anne Carvunis’s website. She is from France. https://carvunislab.csb.pitt.edu/ Also https://www.csb.pitt.edu/people/faculty/anne-ruxandra-carvunis/ This is very provocative. Does this contradict Doug Axe?
It has become clear over the past decade that completely novel protein-coding genes can evolve de novo from the “dark matter” of the genome (non-genic sequences). We are investigating a hypothesis according to which such de novo gene birth involves the existence and translation of transitory genetic elements called “proto-genes”. Our work has shown that cellular networks involve many more biomolecules than we thought, and questioned how translation is regulated. We are now actively investigating how these proto-genes evolve and acquire novel functions. Recent results show that yeast proto-genes can provide a growth advantage to the cell upon overexpression, largely due to the presence of transmembrane domains that arise naturally from non-genic sequences. In another study, we analyzed yeast, fly and human evolution, and determined that most species-specific genes cannot be explained by sequence divergence, although the fraction that emerged de novo remains to be determined. To learn more, check out our recent review (also a Wikipedia page!).
https://carvunislab.csb.pitt.edu/wp-content/uploads/2020/09/protogene_review.pdf https://en.wikipedia.org/wiki/De_novo_gene_birthjerry_{February 26, 2023
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...effectively infinite since this plays right into the hands of the Design Argument...
There is no theoretical limit to the length of an amino-acid sequence but living organisms employ a small subset of the theoretical possible sequences. As the only way to ascertain the usefulness, functionality, of an unknown protein is to test it, I can claim that unknown theoretical protein sequence space is awash with functionality with as much confidence as anyone claiming the opposite. Probability claims are unjustified assertions. Also, a very important point, functionality and sequence of amino acids in a protein are not the same thing. It is perfectly possible for unrelated proteins to have the same function. Also specificity is not required for function. Enzymes can act on more than one substrate, be promiscuous. Specificity can evolve.Alan Fox_{February 26, 2023
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PaV:
...we can’t exactly calculate infinity...
Can you give me a approximate figure for infinity, then?Alan Fox_{February 26, 2023
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Alan Fox: First, Alan, thanks for responding. Second, I think I'll just go down the list of your entries one by one, if that's okay.
So there’s one term we can’t reliably calculate. Now for protein sequences that have function? In all this vast sea of theoretically possible proteins, of the ones not yet having been synthesized neither in vivo nor vitro, how can anyone say whether they have a function in some scenario or not?
I would say that from the fact that we can't exactly calculate infinity we shouldn't conclude that the concept of infinity is of no utility here. Physicists and mathematicians quite often substitute zero for the term 1/infinity. I'm puzzled that you consider 22 raised to the nth power ('n' being a very number) to be effectively infinite since this plays right into the hands of the Design Argument. As to your question, ". . . of the ones not yet having been synthesized neither in vivo nor vitro, how can anyone say whether they have a function in some scenario or not?", isn't this an argument from ignorance? If "fitness" is tied to "biological function," and "biological function" is tied to sequences, to say that something is not synthesized in vivo or in vitro only tells us nothing about what could be functional. No. Hoyle was an astronomer. He had no expertise in biochemistry as far as I know. Fred Hoyle was an outstanding mathematician in addition to being an astronomer. He wrote The Mathematics of Evolution. Cells can't reproduce without the help of cytochrome c. Hence, to enter into the Darwinian realm of "selective death," known as NS, life has to reproduce itself. This means cytochrome c must be present. The question Hoyle asks is how did this protein come about randomly. The mathematics then says that a 105 a.a. long protein has the probability of randomly coming about (assuming it won't be destroyed upon appearance) of 22^ 105. An "astronomical" figure if you can pardon the pun. I'm just a lit bit surprised you weren't aware of his book (although no one seems to want to publish it. Maybe evolutionary biologists aren't interested) Are [you] mixing up your Hoyles, PaV? No, it isn't the "Hoyle's Rule" Hoyle I'm thinking about. No more time now.PaV_{February 25, 2023
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Gould, for his part, seems to rely almost completely on what ‘cannot’ be seen.
Just the opposite. It’s all based on what can be seen. First, there is the change represented by the new species which happens suddenly after eons. Second, there is the mechanism for this change which can be seen in the genome. The basis for the new species has been silently developing over millions of years until it is exapted for expression as a physical difference. Brosius provides a description of the origin of the second part and why it suddenly happens after millions of years of development. It’s very simple and straightforward. The term exaptation was developed by Gould with Elizabeth Vrba. They were more interested in taking current proteins and finding new uses. Brosius explains how exaptation can happen for the development of new proteins. Gould used the word “exapt” several hundred times in his final work, “The Structure of Evolutionary Theory. All these ideas show up in the above OP video. Nothing said in any of Gould’s or Brosius’s work is threatening to ID. I doubt it explains much. But ID should be aware of just what it is. iD can easily debunk it with good research. Here is another article on this.
More Evidence on the Real Nature of Evolutionary DNA Change Our data revealed >280,000 mobile element exaptations common to mammalian genomes covering ~7 Mb..., a considerable expansion from the ~10,000 previously recognized cases. Of the ~1.1 million constrained elements that arose during the 90 million years between the divergence from marsupials and the eutherian radiation, we can trace >19% to mobile element exaptations
https://www.huffpost.com/entry/more-evidence-on-the-real_b_1158228 What this means may be nothing but it should be looked at.jerry_{February 25, 2023
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Jerry:
Again, you obviously do not understand what was claimed as the mechanism for punctuated equilibrium. You are confusing the claimed observations with the proposed mechanism for those observations. You also cite 1970 studies.
I find neither Gould's thesis nor Brosius "proposed mechanism" persuasive. I've scanned an article Brosius wrote recently, in 2019, I believe. I look for stuff of substance. I can't find anything. Is this because I'm biased and my mind is made up? Possibly. However, I don't consider either exaptation by Gould or exaptation by Brosius to be compelling or reasonably plausible. Gould, for his part, seems to rely almost completely on what 'cannot' be seen. His is an inference. So is the "Design Inference." I find the Design Inference plausible. Why? Because intelligence does not act blindly as does nature. And invoking blind forces to explain the origin of life and its subsequent development seems unreasonable based on my experiences in this life. Let's leave it at that. OK?PaV_{February 25, 2023
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Again, what proof is there of “exaptation”? Why aren’t we inundated with examples of it being “demonstrated” to be true
I never said there were lots of examples. Again, you obviously do not understand what was claimed as the mechanism for punctuated equilibrium. You are confusing the claimed observations with the proposed mechanism for those observations. You also cite 1970 studies. Gould was eulogized by an evolutionary biology journal with a special issue in 2005, 30 years after what you cite. See above. Jurgen Brosius was given the premiere spot in that issue. Brosius had collaborated with Gould and obviously knew what he thought. Brosius was recommended by Allen MacNeill who said Darwinian Evolution was dead. This got me curious. I suggest you read what Brosius wrote. As I said it relates to the OP. Whether it explains much is another issue. I never said it did. Though Brosius claims it does. I provided a research approach that would solve everything.jerry_{February 25, 2023
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Are mixing up your Hoyles, PaV?Alan Fox_{February 25, 2023
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I’m sure you’re familiar with Fred Hoyle’s calculations involving cytochrome c, right?
No. Hoyle was an astronomer. He had no expertise in biochemistry as far as I know.Alan Fox_{February 25, 2023
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