Some basic questions about genetic variation

I have some basic questions about genetic variation. My biology knowledge is very basic, so please bear with me. In the traditional Darwinian model, evolution proceeds because randomly occurring genetic variation (because of genetic mutation or recombination) is acted upon by natural selection.

  1. What factors determine the mutation and recombination rates of a particular organism?
  2. Can one separate the speed of mutation and the diversity of mutations? In other words, is it possible for an organism to genetically mutate very fast, but these mutations produce little meaningful phenotypic diversity, making it unable to adapt fast enough to the environment?
  3. Is it conceivable for a universe (or biosphere) to exist where mutation and recombination rates of all organisms are extremely slow, and hence evolution into more complex organisms also becomes difficult or even impossible, because natural selection doesn’t have much genetic material to “work with”?
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Mutation rates are due mostly to errors in replication, which depend on the fidelity of the replication, proofreading, and repair enzymes, which can be changed through evolution. That’s the per replication mutation rate, which differs from the organismal mutation rate in multicellular organisms, because many rounds of cell division happen in the germ line per organismal generation.

Possibly. Depending on how genes interact, there may be a lot of buffering between mutation and phenotype, so that many mutations in functional sequences may not affect phenotype.

Sure, it’s conceivable. It would require very precise replication, which would have a high energy cost and would probably therefore be selected against, and mutations that decreased replication fidelity would be selected until a rough equilibrium between the energy cost of fidelity and the fitness cost of mutation were reached. It’s been suggested that this process explains differences in mutation rate among taxa.

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Thanks, this is helpful. So it seems that variations in mutation rates are due to variations in replication fidelity, which can itself be selected against. However, this just pushes the question back: what is responsible for significant variations in replication fidelity in a population of single-cell organisms, for example?

At face value, it would seem that each single-cell organism is structurally and physically very similar to each other, and so they should have very similar replication fidelity. In other words, because they have a simpler structure, if they exist at all there is a narrower range of possibility for any sort of variation. The only difference I can think of are environmental factors: by chance, organism A happens to be exposed to more UV radiation than organism B, altering its replication fidelity. However, are environmental factors fully responsible for this variation in replication fidelity?

Second, why does precise replication have a high energy cost? Is it related to entropy - meaning that there are more possibilities for a replication to be inaccurate (less fidelity) compared to being error-free (higher fidelity), such that nature “tends” naturally towards less fidelity, similar to how nature tends towards more entropy?

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The replication machinery (which includes proofreading and error correcting) machinery is what explains mutation rate, and this machinery, like everything else in any cell, can vary. That variation can explain most variation in mutation rate. Simplicity of “structure” is not really relevant here.

That’s mostly backwards. Replication fidelity is a function of the machines themselves. Radiation isn’t a factor. Radiation can cause mutations, of course, most of which are repaired, but that doesn’t have anything to do with replication fidelity.

I think you should think of replication as an expensive and elaborate process, controlled by molecular machines that are expensive, elaborate, and–like all proteins everywhere–subject to variation.

I think that is mostly due to the cost of proofreading. DNA replication costs energy. Proofreading and correction costs energy. I doubt this is related to entropy in any clear way: it’s more brutal and basic than that. You can reduce your DNA mutation rate to nearly zero by insisting on the very finest DNA replication machines and the most painstaking proofreading technology with zero tolerance for error. In so doing, you will incur at least two costs: 1) your replication will be slower; and 2) your replication will be more expensive in terms of energy.

So, this is not nature “tending” toward less fidelity. It’s the merciless trial of natural selection and its meticulous balance sheet of costs and benefits.

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Is it possible that populations in changing environments could also be at a disadvantage with TOO much fidelity in DNA replication?

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Disclaimer: I’m more of a physics guy than a biologist, but I’ve taught the basics of evolution to science teachers for many years.

One key point to note is that it used to be assumed that most variation arose through mutation, but the role of gene transfer by viruses and other mechanisms means there are more possible sources of genetic novelty than just mutations.

Variation is always a trade-off with stability. Most mutations are harmful or neutral, a few are beneficial. More mutations means faster mutability but more cancers (which are largely started by misreplication) and more spontaneous abortions and non-viable offspring. Populations will tend to work within this tension.

Rates of mutation and change in a population are likely to be strongly correlated with numbers of generations over time, and therefore shortness of generations. Bacteria can evolve resistance to a new antibiotic very quickly because they have very short lifespans and generations. Lots of mutations and also lots of selections. Something like Galapagos tortoises where the generations might be 25 years… which, come to think of it, is only a little longer than humans… will evolve much more slowly.

On your question 2, I don’t think so: the mutations are more or less random, not directed, so the ratio of harmful to neutral to beneficial mutations is probably not going to be wildly different between species, though there may be something about complexity of the organism and its genome in terms of the space for changes to occur.

In a very, very large universe (which might be part of a multiverse but that’s kind of in-principle unknowable), almost anything is possible. From an evolutionary perspective, though… “don’t start nuttin’, won’t be nuttin’” :wink: That is, it’s not as though you’d end up with a world similar to ours now, and then evolution would stop… except by Special Creation.

If you’re seeking the suggest that our world is such a world… that doesn’t accord with what we observe.

Yes.

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There are other factors. A species with a higher rate of reproduction might be able to afford a higher mutation rate, for example. There is considerable literature on selection acting on replication fidelity. I don’t offhand come up with an entry to this literature, but a bit of search should turn something up.

Not something I can help you with. Again, a literature search would be a good idea.

That’s not really Darwinian, because Darwin knew nothing about mutation. Darwin merely observed heritable variation.

What you’re missing conceptually (and is essential to any of your speculation about kinetics) is the vast reservoir of existing variation. Selection isn’t “waiting” for new mutation and recombination, it has plenty of existing variation to work with for diploid organisms like us.

No one has mentioned the unavoidable factor of keto-enol tautomerization. Here are a couple of basic descriptions:


Again, you have a fundamental misconception that is unfortunately being reinforced by others, because for diploids like us, selection is operating almost entirely on existing variation. If that reservoir is depleted by inbreeding, new mutation is far too slow to provide new diversity and extinction is all but inevitable.

That’s why outbreeding is so important in saving endangered species. If new variation was the critical factor, we’d be mutagenizing them to save them instead.

I’d say that for diploids like us, we already live in such a universe. Without a large reservoir of existing variation, we would be in trouble.

Quantitatively, the contribution of new mutation relative to existing variation is like a drop of water relative to a bathtub of water.

Empirically, we can see this with completely inbred lab mice. For all practical purposes, they do not evolve, because they have zero existing variation and any evolution requires new mutations. A C57BL/6J mouse today is considered to be genetically identical to a C57BL/6J mouse that someone used 30 years ago.

I think that if we are talking about agency, that’s not good language to use. There’s no “error” involved when a transition occurs because of keto-enol tautomerization. It’s a property of the DNA template itself, not any replication enzyme.

And ploidy is a huge factor in that. We have a huge reservoir of existing variation relative to haploid bacteria.

To what extent does keto-enol tautomerization account for the mutation rate? AFAIK, it does not vary.

Keto-enol tautomerization is a function of the template itself, not the replication “machinery.”

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I think it also needs to be mentioned that the power of natural selection to fine-tune the mutation rate is constrained by the effect of genetic drift:

Larry Moran also blogged about it here:

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I considered mentioning population size as another parameter. The larger the population, the better mutation rate can be fine-tuned.

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I don’t know. There are other mutation-causing mechanisms that we weren’t discussing, such as radiation and breakpoints and wobble. Template-specific mechanisms may very well explain some variation in mutation rate between genomes/lineages, but my impression is that such variation would be so template-specific that it would operate at a “gene” level and not a lineage or organism level. There’s a nice example of this below.

Mutation rates are not explained solely by variation in DNA replication machinery, that’s true, and some variation can be attributed to the DNA itself. I’m not sure whether this is a major contributor, and thus not sure how helpful it is in context of Daniel’s question.

Can you explain to me a bit more what this machinery consists of, and which components of it can vary? What explains the variation?

I’m sorry if my questions come off as persistent or odd. As you know I’m a physicist, and have a tendency to want to explain everything in terms of very basic, uniform, fundamental building blocks. For example, in physics or chemistry, two water molecules are exactly the same in structure and behavior - any differences in behavior can be explained by being in different energy levels (whether rotational, vibrational, or electronic) and/or being subjected to different environments. It seems that this atomistic picture doesn’t quite hold in biology, where two cells of the same “type” may not be completely identical in the way two hydrogen atoms or two water molecules are.

Right, but this statement seems to assume that proofreading and correction are needed to ensure a precise replication. In the absence of proofreading and correction methods, it seems that the “default” thing that happens in nature is for the replication to be slightly different from the original.

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I apologize for any imprecision of terms. By “Darwinian” I meant evolutionary science after the Modern Synthesis but before the discovery of neutral evolution, gene drift, and other evolutionary mechanisms present in evolution besides natural selection. (I am not including these other mechanisms in the discussion just for the sake of simplicity.)

Right, but my concern here isn’t about the evolution of humans or complex multicellular organisms with a long evolutionary history. Rather the issue I’m interested in is understanding where this reservoir existing variation ultimately came from, also keeping in mind that all of these complex organisms ultimately developed from unicellular organisms. This is why I’ve been focusing on the simplest case: two unicellular organisms existing in the same environment (perhaps only a short time after life began). First, would such organisms have as much existing genetic variation as complex organisms like mammals? Or would mutation play a larger role in generating new variation for NS to work on?

I personally find it amazing that small differences in replication fidelity in single cell organisms a few billion years ago can ultimately be responsible for the numerous and diverse array of organisms we see existing today. Yes, there’s natural selection, but in my mind natural selection is more of a filter to identify the most useful variations among those already existing in the population. Natural selection wouldn’t be able to do much if say, we lived in a hypothetical world where a single cell organism always automatically replicates into another single cell organism which is exactly like it (similar to a copy-paste operation your computer). But clearly we don’t live in such a world, and I’m trying to understand why without resorting to some God-of-the-gaps explanation.

Well, yes to a certain extend. But replication fidelity of DNA polymerases, even those lacking proofreading mechanisms, is still quite good (at least relatively speaking). I think error rates are on the order of 1 pr. 10.000 to 100.000 bases.

Proofreading and correction mechanisms, plus repair enzymes and so on bring these values up to one error in hundreds of millions to billions of bases.

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In my mind, instead of calling these “errors in replication”, it seems justified to call them “potentially useful variations”. In my simplistic picture, it seems that without these occasional “errors”, NS would have nothing to work with and single cell organisms would have never been able to evolve into something else. These “errors” seem to be the very source of creativity and diversity in nature.

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I don’t see any particular contradiction in the idea that mutations are both errors in the process of replication and necessary for evolution to occur.

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Neither do I. That was just a side comment about potentially different connotations of different terms.

Gotcha. I should add that some mutations (e.g., transposon insertions) are probably not well described by the word “error”. But that seems largely beyond the scope of the current discussion.

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Totally agree. Though in a way my perspective is also rather colored by years of interacting with creationists on the internet, so when we refer to mutations simply as mutations, we get accused of “trying to disguise the meaning”.

The meaning is that they are “blind, accidental, bad copying errors” or something to that effect.

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