Drs. Sanford and Carter respond to PS Scientists

Conversation
130

The whole idea of nearly neutral theory rests on how the variant is propagated in the population. It means that “slightly deleterious” mutations can be masked from natural selection when the effective population size is sufficiently small. The stochasticity of drift then allows deleterious mutations to be propagated as if they were neutral. You’ll also note that this does not guarantee the probability of fixation. If the variant becomes sufficiently deleterious or the effective population size becomes larger, it will be seen and pruned by NS.

GE pretends deleterious mutations can be propagated as if they are neutral by ignoring Ne.

4 Likes
131

Kimura also rejected it in his 1979 paper describing his model of neutral evolution.

No. Some changes are so slight that they will have no impact on phenotype. They are still not strictly neutral, because the information in the genome has still been corrupted. Those tiny corruptions add up to big ones over time.

Absolutely anything that happens in the real world that will affect survival/reproduction, that is NOT a genotype. That’s a lot of stuff.

The other questions you have for me can largely be answered if you simply read Sanford’s book. Let’s just put this on hold until the day you decide to do that. And really, once you have, you can write to Carter & Sanford with your more technical questions at that time.

132

Provide the math.

Because the selection coefficient for such would be several dozen orders of magnitude below anything relevant.

Not for any of the reasons you’ve provided. If you want to provide alternate calculations and explain their derivation, you are welcome to do so.

Offset readily by virtually any degree of beneficial mutation.

Beneficial mutations with selection coefficients around 0.0001 are unlikely to be particularly rare, and are not exactly ‘mega’.

He didn’t claimed that beneficial mutations were extremely rare, indeed he implies a greater frequency than I did (100 generations vs 1000 generations). Such would only need to have a coefficient of 0.00001 (1/10 what I said), which is just barely selectable. So wrong on both counts. But you are also wrong to say:

For reasons I explained in the very quote you responded to!

climatic variation over 25ka to account for a 0.01% difference in fitness anyway

In other words, with ZERO beneficial mutations, you STILL wouldn’t have GE because climate change would alter the DFE.

This is absolutely true, and one of the reasons GE is nonsense, as I just explained. Most nearly neutral deleterious mutations are only nearly neutral and deleterious in a particular context. Change that context, and they may be slightly beneficial and/or no longer nearly neutral. On the other hand:

This is obviously wrong to anyone with a basic understanding of biochemistry. As is the rest of your comment.

4 Likes
133

Only if you redefine “H1N1” as not including the vast majority of the H1N1 subtype.

This year’s vaccines:
For 2020-2021, trivalent (three-component) egg-based vaccines are recommended to contain:

  • A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus (updated)
  • A/Hong Kong/2671/2019 (H3N2)-like virus (updated)
  • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)

Quadrivalent (four-component) egg-based vaccines, which protect against a second lineage of B viruses, are recommended to contain:

  • the three recommended viruses above, plus B/Phuket/3073/2013-like (Yamagata lineage) virus.

For 2020-2021, cell- or recombinant-based vaccines are recommended to contain:

  • A/Hawaii/70/2019 (H1N1)pdm09-like virus (updated)
  • A/Hong Kong/45/2019 (H3N2)-like virus (updated)
  • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)
  • B/Phuket/3073/2013-like (Yamagata lineage) virus

Have you contacted them to explain that those H1N1s need not be included because H1N1 is (according to you) extinct?

3 Likes
134

Yes, but that’s not relevant to the size of the selection coefficient. In fact, the selection coefficient must remain constant in order to determine at what population size selection becomes ineffective.

Don’t know about what the book says, but whatever the population size, there’s a magnitude of selection coefficient that’s invisible to selection, and that would be enough for a GE model. You could pick your favorite Ne, or different Ne’s for different species. That would be necessary to quantify the severity of GE, but not to consider the basic principle.

Are you quite sure?

That was word salad, and it suggests that you don’t understand the GE model either.

Yes, that’s what causes drift. Any stochastic effect contributes to drift. I’m not getting your point.

135

Yes it is. The ability to propagate a mutation through drift is directly proportional to the magnitude of the coefficient and inversely proportional to Ne.

Constancy in determining the Ne required to propagate at some s is not the same as “s being irrelevant.” Both s and Ne are relevant to determining if the mutation is under the purview of drift or NS.

Sorry, but that’s simply not true. GE requires the accumulation of deleterious mutations whose net effect kills the organism. The mutations must evade natural selection at all fitness determinants until the organism suddenly dies. To evade natural selection you must consider s and Ne for the population and mutation. The very moment cumulative s or Ne allows for NS, the mutations will be pruned from the population. The only way for sufficiently deleterious mutations to cause population-level extinction is through extremely small effective population sizes and very large negative selection coefficients–which is not the case for humans.

There is a massive fitness gap between the accumulation of small negative s and the s required to kill the organism.

1 Like
136

I don’t have anything to add. I hope other readers found my explanation helpful.

3 Likes
137

Taking >150,000 generations for flies since creation, using a per generation deleterious mutation rate of 1.2 yields >180,000 deleterious mutations in the current generation of drosophila. This is of course a naïve calculation, but it is in response to Sanford’s more naïve hypothesis, and serves as an order of magnitude constraint. Sanford has not provided any rigorous estimates for thresholds at which catastrophe takes place, nor has he detailed how that would happen at the physiological level. Why are viruses, and flies, still with us, given that even with the outlandish timeframes of YEC, these species and many more should be long extinct were GE true?

Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila

…the divergence between taxa at neutrally evolving sites in the genome is proportional to the per nucleotide mutation rate, u, and this can be used to date speciation events by assuming a molecular clock. The overall rate of occurrence of deleterious mutations in the genome each generation ( U ) appears in theories of nucleotide divergence and polymorphism, the evolution of sex and recombination, and the evolutionary consequences of inbreeding…
Here we directly estimate u in Drosophila melanogaster by scanning 20 million bases of DNA from three sets of mutation accumulation lines by using denaturing high-performance liquid chromatography. From 37 mutation events that we detected, we obtained a mean estimate for u of 8.4 × 10-9 per generation. …By multiplying u by an estimate of the fraction of mutations that are deleterious in natural populations of Drosophila, we estimate that U is 1.2 per diploid genome.

1 Like
138

Note that the coefficient doesn’t depend on Ne, which was my point.

Yes, of course. Not what I was disagreeing about, which was the claim that s depends on Ne (among other variables).

Yes, but you seem to be misunderstanding my point. I’m not sure why.

This isn’t actually true. What’s required is that mutations cumulatively reduce the individual’s absolute fitness below replacement level. The population gets smaller and smaller until it’s extinct.

No, there is no model under which that’s true unless there’s a sizeable variance in the number of these nearly neutral mutations in the population. If the entire population’s absolute fitness is decreasing at about the same rate, no selection happens.

That’s not true. It’s only necessary that the sum of all the tiny little negative selection coefficients is large and that the differences in that sum among individuals is small.

You seem to be arguing for some kind of threshold selection, i.e. the straw that breaks the camel’s back. That seems like a very unrealistic model.

You still don’t seem to understand the GE model, and I don’t understand why. @glipsnort, can you help here?

139

Is the evolutionary force acting on the variant contingent upon s and Ne or not? If this is not your argument, then my apologies.

I am contending that the existence of nearly neutral variants is not sufficient for the GE hypothesis because GE requires that these variants kill the organism. Are you agreeing with this position or disagreeing?

I don’t think that makes sense. If the individual’s fitness is reduced, then we aren’t talking about nearly neutral variants anymore. We are speaking specifically about variants that are affecting the individual. These are not nearly neutral, by definition.

You would need to assume that individuals in the population are receiving the exact same mutations. That is absurd. If the entire population reaches a threshold where the number of nearly neutral mutations suddenly impacts fitness, the population does not simply die and will still explore the mutational search space i.e.–be privy to selection. You need to simultaneously bottle-neck the population and have large negative s in order for the population to die.

No, that’s not quite what I am saying. I am saying at some point s can be selected under some Ne. If the threshold for s is |0.001| and each nearly neutral is -0.0001, then once enough accumulate, NS turns on and can prune. You will never reach the threshold for extinction of -0.05 (or whatever). That threshold is hard-gapped by NS, s, and Ne.

GE requires that NS is turned off at all fitness determinants up to that threshold.

1 Like
140

I can see several possible sources of confusion.
First:

That’s not the case. GE works as long as the absolute fitness of the organism drops below 1.0 – no need for any killing.

Second, @chris_doesdna2018 seems to be assuming that all of the VSD mutations are segregating in the population, whereas if GE were correct, there would be a constant stream of such mutations fixing in the population, permanently reducing the absolute fitness.

Third, I think there’s a confusion about what the selection coefficient means in this case. If an individual allele has a selection coefficient of -0.05% in humans, it can efficiently be selected against because it has a slightly small probability of being passed on in every generation. But that is not the case when s represents the cumulative effect of thousands or millions of alleles. An individual’s fitness may be reduced by 0.05% because of the number of VSDs he or she happens to have, but there is no cumulative effect over subsequent generations for that particular set of VSDs. Or at least none that I can see.

@chris_doesdna2018, I suggest you deal with the model I posted upthread. As I said, it may be wrong, but if it is let’s figure out why it’s wrong.

141

  1. X and y are inversely proportional, and z is directly proportional:

    xy/z=K

  2. But K is a constant that doesn’t vary with X or Y or Z.

@chris_doesdna2018 is stating 1 and @John_Harshman is stating 2. What exactly is the argument?

142

5 posts were split to a new topic: Mendel’s Accountant

143

Does GE hypothesize the extinction of the organism on the basis of lowered fitness from the accumulation of VSDs? I’m curious why we would choose to ignore the predicted outcome of GE to placate the viability of neutral theory.

Do we want to generate a PRS for VSDs and map it to a liability threshold?

Mutations are constant. Segregation should be occurring given that they propagate via drift and will be treated as functionally neutral. Correct or am I missing something [edit: some LD/hitchhiker assumption]?

I’m treating s essentially as narrow-sense heritability i.e.–an additive model. It’s a simplistic assumption, either the coefficients add to modify the risk of fitness decline or they don’t. In either event, GE requires an extinction threshold for s that is crossed before purifying selection can take place. Maybe I’m not quite understanding the set of premises that obviate this issue. If the two thresholds are the same, then we would never be able to observe a patently deleterious variant–as it would kill the population.

I’m saying when:

|s| << 1/(2Ne)

then the variant attached to |s| gets to act neutral and is subjected to drift over NS. The on/off switch for NS is then proportional in magnitude to s and inversely proportional to 2Ne. There is almost certainly a better way for me to word this.

146

It hypothesizes the extinction of the species on the basis of lowered fitness from accumulated VSDs.

I don’t know what that means.

I can’t think of a reason for doing so, but if you can, please explain it.

You seem to be missing that mutations occur, segregate, and then fix. VSDs that fix lower the absolute fitness of the population and cannot be selected against. This progress is (under the hypothesis) progressive. I cannot tell from your response whether you understand that or not.

I’m afraid this is too vague for me to understand. Could you either respond to the model I proposed or offer your own mathematical model of the evolution of fitness in humans assuming, say, 50 new VSDs per birth?

147

Not sure what you mean by “evolutionary force”. Whether drift dominates selection depends on s and Ne. My point, once more, is that s doesn’t depend on Ne.

Disagreeing. GE doesn’t require that variants, or a combination of variants, kill the organism. It requires that variants reduce the population average absolute fitness below 1 recruitment per individual per generation. What’s required in order for selection not to prevent that is that the variance in absolute fitness resulting from nearly neutral alleles is low.

You are confusing absolute fitness with relative fitness. Natural selection acts on relative fitness, but GE is a claim about absolute fitness. You are also confusing individual mutations with an accumulation of mutations, each of negligible effect. The individual variants, if by that you refer to alleles, are nearly neutral. The aggregate of thousands of these alleles would not be neutral except that there is not sufficient variance in the number of them among individuals in the population for there to be differential reproductive success.

No, that’s not true. Not the exact same mutations. A number of these mutations achieve fixation in the population each generation equal to the mutation rate, and the number in a given individual’s genome, mostly inherited from parents, is not significantly different among individuals. The idea is that it takes a difference in number of thousands in order for selection to work.

You understand that this is not a threshold, right? Selection gradually reduces the probability of fixation below the neutral level as Nes becomes more negative. There is no magic point at which selection kicks in. And you still don’t seem to grasp that the variance in the number of nearly neutral alleles much be large in order for selection to operate well enough.

Not clear what you mean there, but I think it’s probably wrong.

Yes, if by the organism you refer to the species.

I don’t know what you mean by that. Who’s ignoring the predicted outcome? Who’s placating anything?

If that’s what you’re saying, in what way are you disagreeing with me? I would say that there is no “on/off switch”, just a fuzzy region in which fixation begins to be at less than the neutral rate.

148

Hi all, first time poster here: just wanted to raise a key point (apologies if this has been mentioned already).

Genetic entropy implicitly assumes that “perfect genomes” are a thing. If perfection is too biblical for you, then “correct genome” will also suffice. Basically, the idea is that there is a “correct” gene sequence for any given gene, and all mutations serve to degrade that archetypal sequence to some extent. And this is incorrect.
A lot of the (otherwise excellent) arguments I’m seeing here seem to be addressing the ‘degradation’ (or not) caused by mutation: the idea that ‘very slightly deleterious mutations’ can accumulate. You can argue that this accumulation is selectable against, but even to suggest accumulation occurs is, at root, a false premise: VSDMs are not accumulating, because ‘perfect starter genomes’ were never a thing, and cannot ever BE a thing. VSDMs are a phenomenon that has existed since the first primitive genomes arose. The starting point has always been “just barely viable”, and from there selection can only lead to either “better”, or “non-viable”. Only one of these outcomes persists.
We are, essentially, built exclusively from the least deleterious VSDMs, filtered through the prism of billions of years.

To even entertain the idea that life began at the “top” and iterated down is to fall into the creationist premise, and this premise is obviously false (I challenge PDP or Sanford to state the perfect height, eye colour, metabolic rate, or skin tone for humans). If instead one starts at the bottom and iterates up, one arrives at the exact same equilibrium point (i.e. where we are now), but one also now has an adequately robust framework to explain how we got here, and a framework within which to place all essentially non-selectable mutations. Very slightly deleterious mutations don’t accumulate…because they’re essentially replacing other very slightly deleterious mutations. Life did not start perfect, and life will never reach perfection (even if such perfection could be defined), it will always iterate to being as good as it can afford, and as crap as it can tolerate.

TL:DR, whenever you consider the sequence for any given gene, don’t fall into the trap of assuming that the canonical sequence is the “best”, and that all mutations mostly either degrade this or leave it unchanged. Life iterates to genes that are “crap but good enough”, and a corollary of this is that such sequences are robust to mutations. Perfection is easy to ruin, but robust mediocrity holds up far, far better.

13 Likes
149

This smacks of the writing of a person who hasn’t yet bothered to read the joint article this post concerns. Or, for that matter, much of any of the rest of the dialogue here up to this point.

150

In which @Sweary_Biochemist’s point has been made repeatedly and been evaded repeatedly.

4 Likes
151

2 posts were split to a new topic: Complaints about doctorates in thread titles