Paul Price: What are the Substantive Critiques of Genetic Entropy?

[Joe_Felsenstein]

I’m going to make a few points, but I do not have time to spend here at PS right now, so don’t expect me to respond much to replies:

1. Yes, there is a disturbingly high mutation rate in humans, which would lead to a too-high mutational load. Possible explanations (a.) we’ve got the mutation rate wrong, or (b.) it was lower in prehistory, or (c.) the Earth is only 6,000 years old, and The End Is Nigh, and almost all of the geology and astronomy of the last 300 years is massively wrong.

2. It is not established that there is a comparable problem in all, or even most, other forms of life.

3. Yes, in any organism where the genome is even moderately well-adapted, more mutations (far more) will be deleterious than will be favorable. That just follows from the genome being much better than random.

4. Having far more deleterious than advantageous mutations does not predict that the same is true of substitutions in evolution. Population genetics calculations show that natural selection can discriminate against deleterious mutations, and do so very strongly. It is telling that PDPrice does not grapple with this.

5. As for weakly selected mutations whose selection coefficients are less than 1/(4N) in absolute value, it is very very hard to collect information on what fraction of those are deleterious.

6. On theoretical grounds, we would expect that as the genome accumulates weakly deleterious mutations, the opportunity for them to be reversed by advantageous mutations would go up (just as the accumulation of minor and not disastrous typos in a book will increase the opportunity for advantageous typos).

7. History: Motoo Kimura and Tomoko Ohta, when they put forward models of probability distributions of advantageous and deleterious mutations, were making an approximation. They were well aware that as mean fitness changed, the distributions would actually change. And no, they were not concerned with rescuing evolutionary biology from collapse, they were actually debating with other population geneticists about what fraction of substitutions, and what fraction of polymorphism, were neutral or nearly-neutral.

8. The 2016 Current Opinions In Pediatrics article linked to by PDPrice is oblivious to the evidence for most of the genome being junk DNA.

[swamidass (S. Joshua Swamidass)]

@Joe_Felsenstein

Yes, there is a disturbingly high mutation rate in humans, which would lead to a too-high mutational load.

I am unaware of this being anything approaching what is required to justify this:

@Joe_Felsenstein

the Earth is only 6,000 years old, and The End Is Nigh, and almost all of the geology and astronomy of the last 300 years is massively wrong.

Honestly, I’m not sure what you mean by “disturbingly high mutation rate in humans.” Perhaps @glipsnort can clarify.

[T_aquaticus]

@PDPrice

• Some try to argue that as more deleterious mutations happen, this opens up the way for more beneficial back-mutations to come in and compensate for them, and at some point an equilibrium is supposed to be reached. This misunderstands the way mutations work at a very fundamental level, as well as greatly misrepresenting the likelihood of back mutations.

It would be helpful if you could clear up this misunderstanding.

@PDPrice

Some try to suggest that mutations are only harmful if they affect the coding region, which in humans is a smaller proportion of the genome.

Who suggests this? I don’t know of any biologists who say this.

@PDPrice

The assumption of “junk dna” was a great embarrassment, and was entirely philosophical from the start. The problem is, as Dan Graur has noted, “If ENCODE is right, evolution is wrong.” Therefore, those who understand this are holding on to their junk dna with white fingernails.

Junk DNA is not an assumption. It is a conclusion drawn from the evidence. Specifically, 90% of the human genome is accumulating mutations at a rate consistent with neutral drift which indicates a lack of function. I think you should read Graur’s entire article to understand why ENCODE got it so wrong:

A recent slew of ENCyclopedia Of DNA Elements (ENCODE) Consortium publications, specifically the article signed by all Consortium members, put forward the idea that more than 80% of the human genome is functional. This claim flies in the face of current estimates according to which the fraction of the genome that is evolutionarily conserved through purifying selection is less than 10%. Thus, according to the ENCODE Consortium, a biological function can be maintained indefinitely without selection, which implies that at least 80 − 10 = 70% of the genome is perfectly invulnerable to deleterious mutations, either because no mutation can ever occur in these “functional” regions or because no mutation in these regions can ever be deleterious. This absurd conclusion was reached through various means, chiefly by employing the seldom used “causal role” definition of biological function and then applying it inconsistently to different biochemical properties, by committing a logical fallacy known as “affirming the consequent,” by failing to appreciate the crucial difference between “junk DNA” and “garbage DNA,” by using analytical methods that yield biased errors and inflate estimates of functionality, by favoring statistical sensitivity over specificity, and by emphasizing statistical significance rather than the magnitude of the effect. Here, we detail the many logical and methodological transgressions involved in assigning functionality to almost every nucleotide in the human genome. The ENCODE results were predicted by one of its authors to necessitate the rewriting of textbooks. We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.
On the Immortality of Television Sets: “Function” in the Human Genome According to the Evolution-Free Gospel of ENCODE | Genome Biology and Evolution | Oxford Academic

@PDPrice

Some acknowledge most of what Sanford says, but then try to retreat into the unknown areas we cannot directly test, while ignoring the implications of what we can test. They suggest that a large fraction of effectively neutral mutations may be beneficial. This was Dr. Schaffner’s tact. He has suggested that all the many and clear acknowledgements in the literature that ‘most mutations are deleterious’ actually only refer to larger-sized mutations, while telling us nothing at all about the small ones. This response I think fails to do justice to the literature itself, which goes much further than this in what it states. It requires us to come to a conclusion that runs contrary to everything we can actually test about mutations. This also ignores the general principle that “it’s easier to break a machine than to improve it”, which means this is highly unlikely to be correct.

A simple way to solve this problem is to point to data that supports your claims. We don’t want to see quotes, but citations of papers that have the actual data. As of now, there is no reason to conclude that the majority of neutral mutations are slightly deleterious to such an extent as to lower fitness as they accumulate.

[sfmatheson]

@Timothy_Horton

if PDPrice will respond to the most substantive critique of Genetic Entropy: that GE is based on the demonstrably false premise all life on Earth came into existence only 6000 years ago.

I am NOT interested in this, and really want the discussion to focus on what @PDPrice wrote. I read his response with deep skepticism, because I am fairly sure that knowledgeable critics of GE are not being accurately represented in those comments. Can we please focus on that?

[PDPrice (Paul Price)]

@Joe_Felsenstein

Yes, there is a disturbingly high mutation rate in humans, which would lead to a too-high mutational load. Possible explanations (a) we’ve got the mutation rate wrong, or (b) it was lower in prehistory, or © the Earth is only 6,000 years old, and The End Is Nigh, and almost all of the geology and astronomy of the last 300 years is massively wrong.

This is a rather large admission, even though it may be couched in sarcasm. Beyond question-begging, is there any evidence for A or B? Why would the mutation rate for humans go up over time (but not for animals)?

@Joe_Felsenstein

It is not established that there is a comparable problem in all, or even most, other forms of life.

Is it not true that for rather selfish reasons, humans are probably more well-studied than most other forms of life, excluding things like lab rats, fruit flies, and bacteria?

@Joe_Felsenstein

Yes, in any organism where the genome is even moderately well-adapted, more mutations (far more) will be deleterious than will be favorable. That just follows from the genome being much better than random.

If neutral theory is correct (and @glipsnort has approved of it here), why would we suspect that the genome would be much better than “random”? Neutral theory states that drift, not selection, is the main driving force of evolution.

@Joe_Felsenstein

Population genetics calculations show that natural selection can discriminate against deleterious mutations, and do so very strongly. It is telling that PDPrice does not grapple with this.

I do grapple with this. What you have just said here is in direct contradiction of neutral theory. The other population geneticist here, Dr. Schaffner, has contradicted you on this point.

@Joe_Felsenstein

As for weakly selected mutations whose selection coefficients are less than 1/(4N) in absolute value, it is very very hard to collect information on what fraction of those are deleterious.

Yes, that’s true, at least directly. However, what reason would we have not to think that the DFE for small mutations would be substantially similar to that for larger ones? As I’ve stated earlier, this is a kind of ‘beneficial mutations of the gaps’ type argument. Everything we can actually test shows a highly negative distribution. So does the general principle that “it’s easier to break a machine than to improve upon it”. This truth isn’t going to suddenly stop existing just because we’re talking about small changes rather than large ones. In fact, I think it applies even more to small changes.

@Joe_Felsenstein

On theoretical grounds, we would expect that as the genome accumulates weakly deleterious mutations, the opportunity for them to be reversed by advantageous mutations would go up (just as the accumulation of minor and not disastrous typos in a book will increase the opportunity for advantageous typos).

I responded to this here. Back mutations would only be helpful if the surrounding context was still intact. But in a case of a huge mutational load such as what you’re suggesting, this would be increasingly unlikely.

@Joe_Felsenstein

History: Motoo Kimura and Tomoko Ohta, when they put forward models of probability distributions of advantageous and deleterious mutations, were making an approximation. They were well aware that as mean fitness changed, the distributions would actually change.

To my knowledge, nobody has produced a DFE that even attempts to model beneficials alongside deleterious mutations. Beneficials are understood to be so rare as to be “outside the model”.

@Joe_Felsenstein

The 2016 Current Opinions In Pediatrics article linked to by PDPrice is oblivious to the evidence for most of the genome being junk DNA.

This is an entire other debate. I do not believe in Junk DNA and neither do an increasing segment of the secular scientific community.

[PDPrice (Paul Price)]

@Joe_Felsenstein

Point 9 in the comment I just made is a mildly-deleterious typo – it never should have existed. I also note that putting the letter “c” in parentheses seems to result in a copyright symbol, another mildly-deleterious mutation.

See how much easier it is to have mildly deleterious mutations than mildly beneficial ones?

[sfmatheson]

@Joe_Felsenstein

Yes, there is a disturbingly high mutation rate in humans, which would lead to a too-high mutational load. Possible explanations (a.) we’ve got the mutation rate wrong, or (b.) it was lower in prehistory, or (c.) the Earth is only 6,000 years old, and The End Is Nigh, and almost all of the geology and astronomy of the last 300 years is massively wrong.

This question, the so-called “mutation load paradox,” is the focus of ongoing research by people I know very well, and these researchers propose that drift barrier theory is the solution. The work has been presented publicly (at Evolution meeting last year) but is currently unpublished.

[swamidass (S. Joshua Swamidass)]

But not as high as to indicate a 6,000 year old earth…

A Resolution of the Mutation Load Paradox in Humans

[evograd (Blogging Graduate Student)]

@PDPrice

If neutral theory is correct (and @glipsnort has approved of it here), why would we suspect that the genome would be much better than “random”? Neutral theory states that drift, not selection, is the main driving force of evolution.

Are you serious here? Do you think neutral theory implies that the genome should be random?

[glipsnort (Steve Schaffner)]

@swamidass

Honestly, I’m not sure what you mean by “disturbingly high mutation rate in humans.” Perhaps @glipsnort can clarify.

I could if I had time – I have to write a talk on data I haven’t analyzed yet(*). There’s a long history here of trying to understand the implications of mutational load for humans, going back in particular to a paper by Nachman and Crowell (Genetics 156: 297–304 (September 2000)), and farther than that to debates between Bruce Wallace and Jim Crow about the subject. It’s what led to Dan Graur’s argument (which he has since retracted in light of the paper below) that most of the human genome couldn’t be functional. I think much of the debate is misguided – and I disagree with Joe’s point 1 – for reasons laid out in this paper: https://academic.oup.com/gbe/article/12/4/273/5762616

(*) About real mutations in real organisms that really kill people. Some things are more important than others.

ETA: Oh, and any calculation of the effect of genetic load has to take into account the difference between hard selection and soft selection and how large the role of each is in purifying selection on humans – which is of course something we don’t really have an estimate of.

[evograd (Blogging Graduate Student)]

@PDPrice

To my knowledge, nobody has produced a DFE that even attempts to model beneficials alongside deleterious mutations.

Have you… Looked?

Literally off the top of my head is this paper I studied back in a population genetics class years ago:

Adaptive Protein Evolution in Animals and the Effective Population Size...

[AlanFox]

Genetic drift is supposed to be random. Thus how can it be adaptive? At some point selection has to kick in.

[sfmatheson]

@AlanFox

Genetic drift is supposed to be random. Thus how can it be adaptive?

That’s easy. The word ‘adaptive’ refers to an outcome. The path to that outcome is not relevant.

[evograd (Blogging Graduate Student)]

@AlanFox

Genetic drift is supposed to be random. Thus how can it be adaptive? At some point selection has to kick in.

Neutral theory doesn’t reject the existence of selection.

[PDPrice (Paul Price)]

So you’re saying that evolution is guided by haphazard “random” changes that just so happen to be adaptive (blind, dumb luck). Neutral theory states that most changes in evolution are not guided by selection. Unsurprisingly, people find this incredible when they finally come to understand what is being said.

[PDPrice (Paul Price)]

@evograd

Neutral theory doesn’t reject the existence of selection.

It does however state that selection plays a lesser role in comparison to drift. Thus, we would not expect the genome to be much better than “random” (as @Joe_Felsenstein said). We would only expect it to be slightly better.

[dsterncardinale]

@PDPrice

I do not believe in Junk DNA and neither do an increasing segment of the secular scientific community.

Evidence for the claim in bold, please. Do note that, for example, the publications put out by ENCODE acknowledge a significant fraction of non-functional DNA.

[AlanFox]

That’s OK then. I was worried for a moment.

[AlanFox]

@sfmatheson

That’s easy. The word ‘adaptive’ refers to an outcome. The path to that outcome is not relevant.

Without bias is there a path?

[davecarlson]

@PDPrice

It does however state that selection plays a lesser role in comparison to drift. Thus, we would not expect the genome to be much better than “random” (as @Joe_Felsenstein said). We would only expect it to be slightly better.

This is really not true at all.