Comment by klmr | Hacker News Reader

Comment by klmr | Hacker News Reader

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GC content (the local ratio of G and C nucleotides, i.e. (#C + #G) / (#A + #C + #G + #T)) varies in patches across certain mammalian genomes. GC content correlates with stability because stacked C–G base pairs are chemically more stable than A–T base pairs. However, while gene density correlates with GC content, gene function is uncorrelated. This means that genes (which tend to be in high-GC regions) in general tend to be (very, very slightly) less susceptible to mutations than non-genic DNA (by contrast, they are vastly less susceptible to mutation than non-genic DNA due to negative selection^1). But the difference in GC content between different genes is purely stochastic, and there’s no mechanism for changing the GC content of a given gene, except by random (!) mutation. This can happen, and it indeed improves the stability of a gene, but the same is true for all genes to the same extent, and it isn’t directed.

^1 I’ve never seen anybody explicitly quantify this but the relative impact of GC content and negative selection on mutation rate must be several orders of magnitude different … at a guess at least thousandfold, more likely millionfold.

> But the difference in GC content between different genes is purely stochastic, and there’s no mechanism for changing the GC content of a given gene, except by random (!) mutation. This can happen, and it indeed improves the stability of a gene, but the same is true for all genes to the same extent, and it isn’t directed.

That seems fine. If some genes are more stable than others, and this can vary by normal random mutation, it can be selected for. I'm still failing to see why this isn't relevant to the current discussion.

Because it’s just stochastic. There’s no mechanism for systematic, guided DNA changes to mutate some genes more than others, which is exactly what I wrote in my initial comment that you took umbrage at. “It can be selected” for only through the blind process of chance, which isn’t really selection at all.

> “It can be selected” for only through the blind process of chance, which isn’t really selection at all.

Selecting is not blind, selecting is sexual or based on survival. The mutation that changes the rate of other mutations is random, but once that mutation occurs it can be selected for via normal means.

Iʼm aware of how evolution works, thanks. I do have a PhD in genetics after all. But this isnʼt what you were talking about here, which is the hypothetical existence of a biological mechanism enacting differential, directional selection.

Evolutionary selection (regardless of whether natural, sexual, artificial or whatever) happens in aggregate over multiple generations, it canʼt account for guided mutations in the germ line that encode “learned” behaviour (which, as my initial comment explained, simply donʼt exist).

I appreciate that you are more well versed in your field than I am. That doesn't mean that you're not making a misstep here. I've known some PhDs and while they often have good points to make in their fields I've also seen some of them eat crow more than once. We're all human.

> But this isnʼt what you were talking about here, which is the hypothetical existence of a biological mechanism enacting differential, directional selection.

It should be noted that I never said directional -- I actually made it explicitly clear in my first post that I was not arguing for a direction, only for modified rates of change: "Note that I haven't suggested that a directional bias exists, just a set of mechanisms for changing variability of different traits." So, I think this is what I've been talking about from the beginning. Perhaps it's due to my lack of familiarity with domain specific language, but I'm not sure that you're understanding what I've been arguing for. Please don't get bogged down in the specifics of this example (it's the pointing finger, not the moon), but I'm not suggesting that cheetahs evolved a tendency to evolve faster running, I'm suggesting that they might have had a period of evolution where a variety of genes related to running were more likely to change in both beneficial and non-beneficial ways, but because faster running was such a beneficial trait it actually made sense for some portion of the population to have offspring who were more likely to have both beneficial and harmful changes happen over the relevant sections of genetic code. In times of less rapid environmental/adversarial change, where stagnation is good enough and the reward for beneficial deviation is more outweighed by the risk of harmful deviation, the rate of change can be toggled back down (again through normal evolution).

1) Do we agree that random mutations of the germline can result in differing rates of change across subsets of the genome?

2) Do we agree that this can affect the viability of offspring?

3) If yes to both of the above, is any component missing for evolution to select for different rates of variability in different subsets of the genome?

> [Being an expert] doesn't mean that you're not making a misstep here.

That’s correct, but we’re not discussing the cutting edge here but relative basics. I’m clearly not articulating myself well but I can assure you that this discussion wouldn’t take place between two biologists because there’s nothing here.

> It should be noted that I never said directional -- I actually made it explicitly clear in my first post that I was not arguing for a direction

You did say that, but, respectfully, you implied directionality — otherwise it would be completely unclear what your initial comment wanted to say, because it seems to specifically have objected to my assertion that no directed changes of the germ line exist.

> Do we agree that random mutations of the germline can result in differing rates of change across subsets of the genome?

Not within a single generation, no. Across evolutionary time, by virtue of selection, yes (that’s in fact the very basis of evolution). But this is irrelevant in the context of this comment thread, started by my initial comment: I asserted that there is no mechanism to encode learned behaviour in the germ line. This would require a direct mediator of mutations on the molecular level, not across evolutionary time but in the here and now. A molecule in the gametes (or their precursor cells). Such a molecule does not exist. Stochastic variation that shapes patterns of mutation across multiple generations is fundamentally a red herring here.

> You did say that, but you meant directionality — otherwise it would be completely unclear what your initial comment wanted to say, because it seems to specifically have objected to my assertion that no directed changes of the germ line exist.

No, I did not mean directionality. I meant what I said, and was very explicit about it. In my first post I quoted the exact bit of your comment I was replying to, which went like this: "So far there’s no known mechanism for systematic, guided DNA changes, and no good reason to assume that such mechanisms exist (on the contrary)." I wasn't even sure if there would be disagreement between us when I originally replied to that, because I'm not sure how broad the definitions you're using for "systematic" and "guided" are. I could see arguing that evolution changing the variability of a subset of the genome is "guided" in some sense, as it can "guide" the process towards more changes in a particular subsystem, but I could also see not arguing that since it lacks direction. Language is mushy. I was trying to qualify your statement, and I posed questions and made statements of my own to that end, but I wasn't sure if my positions were in conflict with yours until you replied. Now I think our positions probably weren't in conflict, but you made assumptions about what I meant to convey based on the larger context of your own post rather than the actual content of mine.

So, to clarify, in that comment by me, “guided” (and, in fact, my whole comment) definitely implies “directional”. But let’s not get hung up on this one word. The comment was about encoding learned experience in the DNA of gametes (i.e. Lamarckism), and the fact that this requires a (nonexistent) mechanism.

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