Directionality in Mutation?

This is definitely interesting. https://www.eurekalert.org/news-releases/941828

Contrary to the widely accepted expectations, the results supported the nonrandom pattern. The HbS mutation originated de novo not only much faster than expected from random mutation, but also much faster in the population (in sub-Saharan Africans as opposed to Europeans) and in the gene (in the beta-globin as opposed to the control delta-globin gene) where it is of adaptive significance. These results upend the traditional example of random mutation and natural selection, turning it into an example of a nonrandom yet non-Lamarckian mutation.

Before I posted this, I decided to re-read this post in an earlier thread - this paper reminded me of it as it also said mutations are non-random.

What do you think this time @Rumraket ?

The authors discuss possibilities in their paper. Paper here: Genome Res | Mobile

Knowing that the HbS mutation is advantageous in heterozygotes under malarial pressure, how shall we interpret these results? One possibility is that, for a reason unrelated to adaptation, some individuals have a genomic fragility in HBB that generates the HbS mutation at a high rate. Accordingly, it is merely a coincidence that HbS provides protection against malaria, even more so if that fragility applies more to Africans.

Another possibility is modifier theory (Feldman and Liberman, 1986; Altenberg et al., 2017), according to which alleles affecting the mutation rate may be favored by selection under certain conditions. (Leigh Jr, 1970; Moxon et al., 1994). However, since the benefit of a
modifier allele that increases the mutation rate is tied to the excess beneficial mutations it helps generate, and since mutations are rare, it is normally expected that, for selection to be effective, it must act on a modifier allele that increases the mutation rate across a long enough stretch of the genome with which it remains linked for a long enough period of time, so that many different
mutations potentially induced by this allele over space and time are factored into its selective benefit (Hodgkinson and Eyre-Walker, 2011; Martincorena and Luscombe, 2013; Walsh and Lynch, 2018). Thus, modifier theory does not predict an increase in the rate of particular DNA mutations at specific base positions, let alone in sexual, complex organisms, nor the complex
genetic and/or epigenetic influences on such mutation rates suggested by the current data (cf. Leigh Jr, 1970; Moxon et al., 1994; Altenberg et al., 2017; Walsh and Lynch, 2018). On the contrary, the “reduction principle”—the first-order principle in modifier theory—underscores
the general difficulty of accounting for increased mutation rates (Feldman and Liberman, 1986;
Altenberg et al., 2017).

Finally, a recently proposed theory predicted that mutation-specific origination rates are influenced by the complex genetic and epigenetic background, that genetic relatedness in mutational tendencies exist, and that the HbS mutation arises more frequently in Africans than in Europeans (Livnat, 2013, 2017). It holds that novelty in evolution arises from emergent interactions which are then simplified through the generations by mutational mechanisms while being checked by natural selection (Livnat, 2017), one hypothetical example being that A→I RNA editing can mechanistically increase the A→G mutation rate in the corresponding positions (cf. Popitsch et al., 2020). Based on these and other previous work (Livnat and Pa-padimitriou, 2016), we hypothesize that recurring, evolved processes acting on DNA and/or RNA through epigenetic modifications (Klose and Bird, 2006), RNA editing (Nishikura, 2010)
and other mechanisms may lead directly to their own replacement and simplification via DNA mutations that arise in the course of evolution from these processes’ molecular nature, mechanistically linking regulatory activity with structural mutational changes—though whether and by what specific mechanism this “replacement” hypothesis explains the HbS case specifically (alternative decoding of A→I editing, Licht et al. 2019, or other mechanisms) is yet to be investigated. This raises the possibility that a mutation of adaptive value such as the HbS one need not initiate the process of adaptation but can arise later in an evolutionary process where adaptations and mutation-specific rates jointly evolve (Livnat, 2013, 2017), and thus studies on the fundamental nature of mutation need to test for not only a short-term response to environmental
pressures (Luria and Delbruck, 1943; Cairns et al., 1988) but also a long-term one.

Unlike previous methods that could explore only diffuse relationships between long-term selection pressures and the evolution of GWA mutation rates, the present method offers the refined ability needed to explore such relationships, if they exist, at the mutation-specific resolution. Because this method examines the mutation-specific resolution for the first time, it provides only initial estimates of mutation rates, which will require further investigation and refinement. Furthermore, it cannot be applied currently to all mutations, because it requires a special RE for each ROI. However, given the numerous REs available and their short recognition sequences, which imply large representation of these sequences across the genome, it likely applies across many loci and organisms. Therefore, some of the most important tasks now are to examine the high-resolution mutation rate variation across additional loci of interest and to explore the molecular mechanisms responsible.

For my part, I would like to see evidence it’s not a coincidence… :slightly_smiling_face:

There are reasons to be cautious here. What you link to and quote is a press release, and they’re famous for hype. The actual paper is much more circumspect in its conclusions, and rightly so given the limited data. Every third press release for a paper in evolutionary biology purports to overthrow Darwin. Don’t take it too seriously.

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Some previous discussion of this paper here:

I don’t find hyping the hype of publicists to be interesting. Why do you?

If it is such a groundbreaking study, why was it published in Genome Research and not a much higher-impact journal? That’s another tell.

Mutations are ONLY random with respect to fitness. They are decidedly nonrandom with respect to location, direction (transitions are far more common than transversions), and their ability to be induced by mutagens.

Why did you copy so much of the discussion? Was it more interesting to you than the actual results, perhaps?

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Different paper. I was just trying to explain that this paper might upend what @Rumraket was saying even though the other one didn’t.

I messed up the quotes. I just fixed that. So you can see I quoted the discussion where they were more circumspect and I also mentioned I’d like to see that evidence that it’s not a coincidence.

If I understand the paper correctly, it is saying they may not random with respect to fitness if the higher occurrence correlating with the environment isn’t coincidence.

That was the part I figured would be more interesting to discuss, yes. But the results were also interesting. It could be quite something if epigenetics or another factor has this much affect on mutation occurrence. But a lot more research has to be done obviously.

There isn’t any, as best I can tell.

Yes, different genes may mutate at different rates. But that is not directionality. It is just natural selection at work.

It looks like a better candidate than the other one at first glance. Though the mechanisms here are unknown, there is a small handful of examples known of “targeted” adaptive mutations.

IIRC in one study with a particular species of bacteria, they had some gene which - if turned on(it was induced by some particular environment) - would produce some protein that targeted some other specific genomic locus for a mutation that was adaptive in that environment. Not sure if I remember the details exactly but it was something to that effect. And that would definitely qualify as sort of “directed” mutation.
It’s conceivable something similar could be at work here.

And there’s nothing in principle that prevents the evolution of such sequence-targeting mechanisms. For example by some more non-specific DNA binding/editing protein that binds and some times edits lots of places in the genome, evolving higher specificity and activity. It’s just that the vast, vast majority of mutations are not the product of such environmentally controlled, highly specific mutation inducing mechanisms. If they were then it becomes a total mystery why the majority of spontaneous mutations would be deleterious. That only really makes sense if they aren’t directed to be adaptive through some targeting mechanism.

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CRISPR/Cas9 is probably the best example of non-random mutations, IMHO. In its natural state in living species, this is very specific, site directed source of mutations with a very clear purpose (i.e. phage immunity).

Exactly.

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On this, it also bears mentioning that there’s nothing about mutations being random with respect to fitness which is essential to evolutionary theory. I often see suggestions that some sort of non-randomness with respect to fitness is somehow fatal to “Darwinism” (as the people who make these suggestions are great fans of that word). But it’s not. The significance of mutations being “random” is that the fact that evolution can work despite mutations being random shows that there doesn’t need to be some other unknown guiding principle at work. But nothing about evolutionary theory (or “Darwinism,” if you swing that way) REQUIRES that mutations be random.

Robert Shedinger’s horrid book The Mystery of Evolutionary Mechanisms is one of the creationist works that makes that mistake. It’s been a while since I read it, but it seems to me that at one point he makes reference to some study which showed nothing more than that environmental stresses of some sort caused elevated mutation rates in some particular species, resulting in an improved likelihood of some adaptive mutation which helped the species survive those stresses. Not being terribly bright, at least in terms of his ability to understand biology, Shedinger couldn’t help but see the Noodly Appendages of the Flying Spaghetti Monster in that, but of course there was no need for that hypothesis.

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Are you perhaps referring to this?

I find two controls to be a grossly insufficient basis for the authors’ expansive claims. There’s also another problem I see: if you look at Table 1, five of the 20A>T mutations were in only one of the samples. Two other samples had 2 each, the rest none. If this was a truly population-level phenomenon, that distribution looks fishy. @Dan_Eastwood, what do you think?

@thoughtful, this is how scientists examine evidence. It often doesn’t support the text.

Another thing that raises alarm bells:

Since one of the samples was a mixture from two African donors with a total number of cells similar to the other African samples, we consider it here as a single sample of mixed African origins,…

How would that mixing happen?

But copying it isn’t discussing it. What were you planning to discuss? How about those anomalies in the evidence?

Why would you like to see “evidence it’s not a coincidence” when you’re not looking at any evidence the other way?

Agree for different reasons.

Since one of the samples was a mixture from two African donors with a total number of cells similar to the other African samples, we consider it here as a single sample of mixed African origins, bringing the total to 11 samples, 7 from African and 4 from European donors (Supplemental Table S1).

11 donors are sufficient for demonstrating the lab technique, but not for representing continental populations. The results could by perfectly correct, but I wouldn’t think it credible on the basis of this study alone.
Two controls is also problematic.

This is a methods paper, demonstrating the accuracy of this new lab technique. Yes they find differences in mutations rates, but I take it that is not a complete surprise. What this says is that the new method can tease out difference better than old methods.

We refer to this whole method as Mutation Enrichment followed by upscaled Maximum Depth Sequencing—MEMDS

The enrichment process is interesting …

Importantly for the mutation rate calculation, we keep track of the number of WT molecules removed by accurately calculating the protected mutants’ enrichment factor on a per sample basis

… but adjusting counts based on the enrichment factor may also increase the variance. That is educated speculation, but I would ask about this if I were a statistical reviewer.

I am annoyed to see they report p-values in scientific notation - the magnitude of p-values is not interesting. I don’t see the supplementary tables, and that’s where the really juicy numbers will be.

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Funny, I raised that paper almost 4 years ago in a different “are mutations random?” thread: Mark: Are Mutations Random? - #58 by evograd

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Agreed.

I’m thinking about cross-contamination, a huge problem whenever PCR is involved.

Yes, I’m sure it started that way, but now they’re touting it as much more.

Yup.

You’d also ask about it if you’d done a lot of PCR during the past 34 years and don’t claim any statistical expertise.

I used to see a lot of stats done wrong with PCR (like t-tests on fold change), but about 10 years ago everyone caught on to the correct methods.

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