The significance of random mutations in the Origins debate

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Hello all. I’m new here and this is my first post.
Firstly, I’d like to thank Dr. Joshua Swamidass for creating this wonderful platform and giving opportunity for everyone to post their personal opinions.

I’m a Design supporter as I’m convinced that design is the most rational explanation for the origin of specified biological information as opposed to strictly naturalistic explanations.
However, I neither deny evolution altogether nor the scientifically-determined age of fossils. I hold that organisms are designed to evolve with varying time and conditions.

Popular books on Evolution and college textbooks have long been teaching that variations occur by chance or random accidents. All genetic mutations, they taught, are unintended disruptions in the genetic code.

References:
[1] “Where does this genetic variation come from? Mutations— accidental changes in the sequence of DNA that usually occur as errors when the molecule is copied during cell division.”
(Why Evolution is True, 2009)
[2] “Traditional thinking holds that mutation happens by accident and then spreads in the population by either natural selection or random genetic drift.”
(Doi: https://doi.org/10.1007/s11692-017-9407-x)

Of course, some mutations occur by chance. For example, mutations introduced by DNA copying errors, reactive oxygen species and environmental factors.
However, are all heritable genetic changes unintended disruptions of the genetic code? Do organisms have the ability to generate variations? The answer to this question has great implications in the origins debate, I believe.

Think of meiotic recombination, a process that is known to us for decades. The new allele combinations produced through this process may be random but the event itself is not. Its a programmed and regulated process orchestrated by the cell that helps to generate variations. Its mediated by multiple biomolecules within the cell. In other words, the cell or the organism’s physiology has an active role in the generation of heritable genetic variations.

Somatic Hypermutation, a programmed process of mutation that has been known to us since 1980s, also points to the cellular capability to generate alterations in DNA. Although it doesn’t generate heritable variations, SHM shows that cells can target and mutate specific gene segments at specific time.

The CRISPR-Cas-system, which facilitates adaptive immunity in bacteria and archae, also illustrates the built-in cellular ability to modify genome.

Thanks to the advancement in biology, now we know of more built-in programmed mechanisms that generate heritable variations (especially during stressful & changing environments).

■ Stress induced mutations aid organisms to adapt to a stressful condition

References:
:black_small_square:︎ In prokaryotes -
This 2004 work showed that
preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic E coli unable to evolve resistance against the antibiotics ciprofloxacin & rifampicin.
(doi:10.1371/journal.pbio.0030176)

:black_small_square:︎ In Eukaryotes -
This 2014 work showed that induced mutations in yeast cells help them adapt to a challenging environment.
(doi:10.1371/journal.pone.0111133)

:black_small_square:︎In humans -
This 2021 study found that de-novo HbS mutation rates are substantially higher in people living in malaria-prone regions.
(doi: 10.1101/gr.276103.121)

Some had criticized the later study. (See: Brian Charlesworth on the errors of a new paper supposedly showing that a fundamental assumption of neo-Darwinian evolution is wrong – Why Evolution Is True)
However, the authors responded by showing that those criticisms do not hold merit.
(See: https://www.livnatlab.com/blog)

A search on Pubmed will list hundreds of studies & reviews on Stress-induced mutagenesis. I recommend reading them to get a better understanding.
For example, refer this 2022 review paper: (doi: https://doi.org/10.1128/mbio.01074-22)

An important thing to keep in mind is, I do not claim that all mutations generated by this mechanisms are evolutionarily significant. Mutations generated so may or may not end up contributing to the evolution of organism. The key point is that cellular physiology has an active role in the generation of these variations rather than being passive. They are not random accidents or unintended disruptions in the genetic code.

■ Stress induced Transposable Element insertion in Drosophila contributes to resistance against oxidative stress.
(Doi: https://doi.org/10.1111/mec.12711)

Mobile DNA elements have been found to be playing significant role in rewiring and innovating transcriptional regulatory networks in evolution. They can reposition promoters, enhancers, heterochromatin markers, insulators, splicing signals, and other cis-acting control elements that are embedded in their sequences.
Refer this review paper to learn more: (doi: Regulatory activities of transposable elements: from conflicts to benefits | Nature Reviews Genetics)

■ CNV generated through recombination offers anti-fungal drug resistance to Candida (doi: https://doi.org/10.7554/eLife.58349)

■ Horizontal Gene Transfer

■ Transgenerational Inheritance of Epigenetic modifications.
For example, this 2011 study found the multigenerational Inheritance of extrachromosomal information in the form of small RNAs, viRNAs, which are induced by an episode of viral replication and which are propagated through the germline in a non-template-dependent manner.
(Doi: https://doi.org/10.1016/j.cell.2011.10.042)

■ Evolutionary changes driven by Developmental plasticity which is an intrinsic property of developmental systems.

Examples: (a) The morphology of white water-buttercup (Ranunculus aquatilis) leaves depends on their environment. Submerged leaves are branched into 20 or more thread-like segments. Floating or exposed leaves are scalloped.
(b) The water flea Daphnia longicephala develops protective crests and tail spines in response to its water bug predator, Notonecta.
(c) Adaptive Transgenerational plasticity in the plant Polygonun persicaria in drought.

■ Ability to mask/buffer Cryptic genetic variations in normal conditions and releasing them during stress or particular environments
Example: (doi: https://doi.org/10.1126/science.1240276)

■ Genome restructuring mediated by TEs during interspecific hybridization
(Doi: Drosophila Females Undergo Genome Expansion after Interspecific Hybridization | Genome Biology and Evolution | Oxford Academic)

■ Modular organization of biological systems (such as gene regulatory networks, protein interaction and metabolic pathways) promotes Evolvability.

In all the aforementioned mechanisms, evolution begins with a minimum level of cellular complexity. Several information-rich biomolecules, especially a number of different proteins, are necessary for the generation of variations through these processes. For example, refer this review to learn about the biomolecules involved in Horizontal Gene Transfer - (Doi: https://doi.org/10.3389/fmicb.2018.02154)

Evolutionary innovations mediated by all the aforementioned mechanisms are entirely compatible with Intelligent Design theory because its the organismal built-in mechanisms that generate variations and promote evolution. In other words, organisms are designed to evolve with varying time and conditions.
This is the reason why the concepts put forwarded by biologists such as James Shapiro and Rosenberg are gaining wide acceptance among Design proponents. (although all these biologists are unsupportive or even critics of ID). No sensible design proponent would argue against evolution mediated by built-in mechanisms. Fact is, until a few years back, no design proponent had thought of this possibility. The ability of cell/organismal physiology had been greatly underappreciated.

■ In addition to these, there is another important and widespread mechanism of evolution that too is compatible with Intelligent Design. Evolution by loss-of-function mutations or Reductive Evolution. Its top-down evolution since it begins with greater biological information content.
Examples: (a) Loss of function in SLC30A8 is associated with reduced risk of type 2 diabetes in humans.
(b) Experimental evolution in Pseudomonas aeruginosa resulted repeatedly in loss-of-function mutations in nfxB, conferring antibiotic resistance.

Overwhelming number of scientific papers points to the active role of organisms’ physiology in the process of evolution. Although the authors of all aforementioned papers believe that the ability to evolve itself was evolved, they do not offer an explanation. In fact how can they? If evolution we observe in real-time require sophisticated cellular mechanisms, one cannot invoke evolution to explain the origin of these cellular tools in the first place. Doing so would be a logical contradiction. This raises a challenge for design deniers - the evolutionary kick off.

EVOLUTIONARY KICK OFF - an underappreciated problem in the Origins debate

In my opinion, this is one of the best arguments that a design proponent can put forward in the Origins debate. However, as far as I know, this problem has been hardly identified or described in any design literature.
The concept is simple: According to naturalistic explanations, the process of biological evolution must have begun once the first (hypothetical) self-replicating systems originated in the primitive earth. Evolution had to kick off from that point. Its on the shoulders of evolution to form the first cellular life from these primitive self-replicating systems. In fact, its very first task.
Keep in mind that all the aforementioned built-in mechanisms such as horizontal gene transfer, transposition, recombination and stress induced mutagenesis are non-existent for a primitive self-replicating system. The only evolutionary mechanism that can be invoked is random accidental mutations getting fixed by selection or drift. But do we know of any significant biological innovation that originated solely through this mechanism of evolution? As far as I know, no emperical data suggests so.
In a 2021 Bioessays paper, prominent evolutionary biologists explains:

"…Our understanding of the origin of novel complex traits remains poor, apart from the realization that key evolutionary innovations such as the vertebrate eye, the insect wing, and the mammalian placenta cannot be explained by selection on random genetic mutations per se."
(doi: 10.1002/bies.202100185)

If selection on random genetic mutations by itself couldn’t have formed key evolutionary innovations such as eye, wings and placenta, how on earth it could have produced an enormously complex cell from a hypothetical primitive self-replicating system? This is the ‘evolutionary kick off challenge’ in brief.

I welcome all design deniers on this forum to give your thoughts on the above described ‘kick off’ problem. I’d greatly value healthy criticisms too.

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  1. You are the denier here.
  2. Mutations are, and have always been, random ONLY with respect to fitness, NEVER with respect to time, frequency, direction, et al. Your framing is objectively false. You’ve been fooled by pseudoscientific politicoreligious apologetics. Please stop regurgitating them.
  3. As just one example, somatic hypermutation does not occur in the way you described. Its complexity, and the enormous human suffering caused by it, makes its evolution much more obvious.
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All of them. No reference you give contains a counterexample.

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I mean think about it. If you think an increased RATE of mutations makes those mutations non-random, then why weren’t they already non-random before the rate was increased? At what frequency do mutations graduate from random to non-random? A mutation once in every 10 000 basepairs? Once in every 100 000 bp?

Clearly any answer would be completely arbitrary.

If transposons insert all over the place, but at some locations at a slightly elevated rate, while still being rather scattershot and it still takes a large number of different ones to be inserted in different locations in different individuals, how is that non-random? Just because the rate was increased it somehow crossed over from random to non-random? That doesn’t make sense.

No. Mutations are random. As long as chance is involved, as in it takes many to be generated, spread out among different individuals in a population (whether those are immune cells, bacteria in a colony or broth, or fruit flies in a swarm), and that the low odds of a beneficial mutation is beat by simply having many such mutations generated, then it is random by any sensible definition of that concept.

Whether I roll 5 dice 10 times, or 50 dice once, each dice roll is still random. The rate is irrelevant. The fact that someone can reliably make me roll 50 dice by putting a gun to my head doesn’t make the individual rolls non-random. Me rolling dice being in that way “induced” doesn’t make the rolls non-random.

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I think you have to understand what random in random mutation means, and you need to look more closely at what your references say.

In every case it took really large numbers of mutations to be generated, with the vast majority being neutral or deleterious, before some luckly individual suffered a beneficial mutation. That’s how we know they are random mutations. If it takes many individuals in a population to suffer different mutations, and only a small minority of individuals get the “right” ones that are adaptive, then those mutations are random.

It doesn’t matter that there was some sort of environmental feedback that increased the rate of mutations (like elevating the rate at which transposable elements scattershoot some locus, or caused substitutions and/or small indels in somatic hypermutation), because it still took a huge number of mutations generated in blindness to their future effect to ensure that in that large collection of mutations, one or a few individuals happened to get lucky and get an adaptive one.

That means all those “induced mutations” processes are still random, because they’re blind to the future and rely on generating large numbers of different mutations in different individuals, to sort of “guarantee” one with a positive fitness effect will be found.

So it seems you’ve fundamentally misunderstood what it means for a mutation to be random.

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I’ll start my comment by mentioning that I am not a biologist. I’m a mathematician. The biologists may disagree with some of my opinions.

One issue here, is that ID proponents won’t give a clear definition of what they mean by “design”. And without such a clear definition, arguments about design cannot get anywhere.

I can welcome that.

Yes, mutations are often described as copying errors. I try to avoid saying that. To say that there was a copying error is to say that there was an intention to do things one way but they turned out differently. However, we do not know anything about intentions of individual cells, so we should not be saying that.

Let me comment on variation. It is hard to say what it means. Suppose I were manufacturing rulers. And suppose that I had to occasionally adjust the machinery so that the future rulers would be correct. I could use a recently made ruler for this adjustment. But if that is how I did it, using the current generation to calibrate the next generation of rulers, we would expect the calibration to drift. We avoid this by having an international standard for length, and we calibrate in accordance with this international standard. But the international standard is, itself, just a convention. At one time, the standard was based on the length of a platinum rod. More recently, it is based on the velocity of light and on a standard for time via the atomic clock. So even our standards can change. What this suggests are that there are no completely independent standards, so some sort of variation is natural. We judge variation only in terms of our own conventions.

If we look at biology from this perspective, then I’m suspecting that the use of DNA is an attempt by biological systems to introduce their own conventions. The genome can be seen as a kind of system of conventions which is passed down the inheritance tree.

Just as we tweak our conventions from time to time, it is possible that biological systems tweak their conventions. So mutations could be convention tweaking.

If a cell is tweaking its conventions, it could try systematically testing a variety of tweaks to see what works best. But that would require coordination between many cells. Or, instead, it could use random tweak which avoids the need for any central coordination. This is how I tend to see the randomness of mutations.

I happen to think development plasticity is important. But changes due to development plasticity do not find their way into the genome, so cannot explain most of evolutionary change, except perhaps via the Baldwin effect.

I don’t agree with that. It seems to me that there could have been an early protolife before there was replication. And there could have already been some evolution at that stage. The ability to replicate could itself be something that evolved.

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Initial thoughts:

What was designed, how, when and by who? How do you know? You don’t actually say. There’s nothing to argue against.

Also, what “specified biological information”? What is specified? Where is it specified?

“prominent evolutionary biologists” that you don’t name is a massive red flag.

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Hello @Midhun, and Welcome to Peaceful Science :slight_smile:

There are lots of design supporters out there, but there is an important distinction to be made between those who support design as a matter of faith and those who believe it can be supported scientifically.

For Intelligent Design to be a scientific theory there must first be a hypothesis to be falsified, or which at least has the potential to be falsified. The primary objection to ID as science is that is does not pose testable hypotheses. How would you propose to falsify a hypothesis that organisms are designed to evolve?

In so many words, you are repeating an old failed argument that new function or new information cannot evolve. There are very good reasons why this argument fails, and this has been the topic of discussion here many times before. As student of life science you should seek to understand why this argument fails, rather that repeating the failed argument.

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Suggestion: Let’s post some links to previous discussion to allow @Midhun to catch up with current discussion, rather than repeat all that discussion here.

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@Midhun
This might be a place to start, a video of Nick Lane on the most current thinking in Origins of Life research, which is a good starting point for defining which functions are fundamental and which are evolved. It’s not a short video, about an hour skipping the introduction, but should be worth your time.

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Plasticity driven variations are found to be transgenerational in a number of cases. For eg, refer the 3rd study under that paragraph (Adaptive Transgenerational Plasticity in an Annual Plant: Grandparental and Parental Drought Stress Enhance Performance of Seedlings in Dry Soil | Integrative and Comparative Biology | Oxford Academic).
Another point to keep in mind is that the plasticity response of an organism is not solely dependent on the genotype. Previously inherited environmental information can also influence the reaction. That is, history of previously inherited non-genetic information can influence future plastic responses and the phenotypes produced. In that way, plasticity is able to produce irreversible variations.

Origin of life models differ with respect to the proposed sequence of events. The leading proponents of RNA world, the most extensively investigated OOL hypothesis, propose that biological evolution started once a self-replicating system of sufficient fidelity had arose.
Even if evolution begun in an earlier stage as speculated by you, it does not change my arguement much.

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What I mean by “Design” is the following dictionary rendering

Screenshot_20230305-194603_Chrome
Screenshot_20230305-194603_Chrome1080×533 67.2 KB

To know more, please read the following encyclopedia article.
https://www.newworldencyclopedia.org/entry/Intelligent_design

Okay fine. But I’m afraid you are speculating too much and gone far away from currently available emperical data.

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Please read again the paragraph that starts with “An important thing to keep in mind is”

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I’m pretty sure you haven’t read any of the references. The very first study itself explicitly speaks about the role of induced mutation in the evolution of antibiotic resistance. They found that antibiotic resistance-conferring mutations required the induction of certain proteins involved in microbe’s stress response.

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Please be specific. Which statement of mine about mutations do you disagree with? Would you please quote

Again please quote my statement about SHM you are disagreeing with.

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He included lots of references in his initial post, most of them legit as far as I can tell, and I doubt that is the entirety of his reading. So I doubt that lack of information is his problem.

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Do you know of any that are nonrandom with respect to fitness?

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How does that contradict anything I said?

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That does not tell us much.

Here are some questions:

  • Does a beaver design a dam?

  • Does a bird design a nest?

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All of them. Changes over time or by location do not contact the fact that they are random ONLY with respect to fitness.

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