Friday, July 24, 2015

John Parrington and the genetic load argument

We are discussing John Parrington's book The Deeper Genome: Why there is more to the human genome than meets the eye. This is the first of five posts on: Five Things You Should Know if You Want to Participate in the Junk DNA Debate

1. Genetic load (this post)
John Parrington and the genetic load argument
2. C-Value paradox
John Parrington and the c-value paradox
3. Modern evolutionary theory
John Parrington and modern evolutionary theory
4. Pseudogenes and broken genes are junk
John Parrington discusses pseudogenes and broken genes
5. Most of the genome is not conserved
John Parrington discusses genome sequence conservation


1. Genetic load

The genetic load argument has been around for 50 years. It's why experts did not expect a huge number of genes when the genome sequence was published. It's why the sequence of most of our genome must be irrelevant from an evolutionary perspective.

This argument does not rule out bulk DNA hypotheses but it does rule out all those functions that require specific sequences in order to confer biological function. This includes the speculation that most transcripts have a function and it includes the speculation that there's a vast amount of regulatory sequence in our genome. Chapter 5 of The Deeper Genome is all about the importance of regulatory RNAs.
So, starting from a failed attempt top turn a petunia purple, the discovery of RNA interference has revealed a whole new network of gene regulation mediated by RNAs and operating in parallel to the more established one of protein regulatory factors. ... Studies have revealed that a surprising 60 per cent of miRNAs turn out to be recycled introns, with the remainder being generated from the regions between genes. Yet these were parts of the genome formerly viewed as junk. Does this mean we need a reconsideration of this question? This is an issue we will discuss in Chapter 6, in particular with regard to the ENCODE project ...
The implication here is that a substantial part of the genome is devoted to the production of regulatory RNAs. Presumably, the sequences of those RNAs are important. But this conflicts with the genetic load argument unless we're only talking about an insignificant fraction of the genome.

But that's only one part of Parrington's argument against junk DNA. Here's the summary from the last Chapter ("Conclusion") ...
As we've discussed in this book, a major part of the debate about the ENCODE findings has focused on the question of what proportion of the genome is functional. Given that the two sides of this debate use quite different criteria to assess functionality it is likely that it will be some time before we have a clearer idea about who is the most correct in this debate. Yet, in framing the debate in this quantitative way, there is a danger that we might lose sight of an exciting qualitative shift that has been taking place in biology over the past decade or so. So a previous emphasis on a linear flow of information, from DNA to RNA to protein through a genetic code, is now giving way to a much more complex picture in which multiple codes are superimposed on one another. Such a viewpoint sees the gene as more than just a protein-coding unit; instead it can equally be seen as an accumulation of chemical modifications in the DNA or its associated histones, a site for non-coding RNA synthesis, or a nexus in a 3D network. Moreover, since we now know that multiple sites in the genome outside the protein-coding regions can produce RNAs, and that even many pseudo-genes are turning out to be functional, the very question of what constitutes a gene is now being challenged. Or, as Ed Weiss at the University of Pennsylvania recently put it, 'the concept of a gene is shredding.' Such is the nature of the shift that now we face the challenge of not just recognizing the true scale of this complexity, but explaining how it all comes together to make a living, functioning, human being.
I've already addressed some of the fuzzy thinking in this paragraph [The fuzzy thinking of John Parrington: The Central Dogma and The fuzzy thinking of John Parrington: pervasive transcription]. The point I want to make here is that Parrington's arguments for function in the genome require a great deal of sequence information. They all conflict with the genetic load argument.

Parrington doesn't cover the genetic load argument at all in his book. I don't know why since it seems very relevant. We could not survive as a species if the sequence of most of our genome was important for biological function.


14 comments :

  1. Wikipedia says: "Genetic load is the difference between the fitness of the theoretically optimal genotype and the fitness of the observed average genotype in a population. "

    This seems a bit odd. I didn't know that there was a theoretical optimum.

    Is there a better definition? Are the sequence differences within species or within genes. Or what?

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  2. Larry,

    ...an accumulation of chemical modifications in the DNA of its associated histones, a site for non-coding RNA synthesis, of a nexus in a 3D network

    This makes even less sense to me than I imagine it's supposed to. Have you by any chance changed "or" to "of", twice? Because I'm pretty sure histones don't have DNA, and I'm pretty sure that RNA synthesis doesn't produce a nexus in a 3D network.

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    1. Thanks. I had changed an "or" to an "of" twice. Now that I've corrected it, I'm sure you can see that it makes sense.

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    2. Well, more sense at least. Now it's just wrong instead of not even wrong.

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    3. Larry needs to start removing your posts more quickly. I think he should remove only the posts that say nothing, but that does seem to be all of them.

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  3. The Deeper Genome: Why there is more to the human genome than meets the eye

    Such is the nature of the shift that now we face the challenge of not just recognizing the true scale of this complexity, but explaining how it all comes together to make a living, functioning, human being.

    Hey, what about living things other than Homo sapiens? Are humans really so exceptional genome-wise? I thought the human genome was a genome rather than the genome.

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  4. "We could not survive as a species if the sequence of most of our genome was important for biological function. "

    Yes we can if the functions are deeply redundant, which indeed they are, and also if mutations are not completely random but are restricted to avoid damaging function. GWAS and other studies have shown fault tolerance and redundancy in the genome. The fact a region can tolerate mutation is evidence of functional fault tolerance, not lack of functional role. For example, there is a 2010 paper on incongruent redundancy experiments that show functionality but also tolerance to mutational knockout.

    If function is discovered, in light of the genetic load problem, this is evidence of function that arrived independent of natural selection. Something can be functional without being selectable, especially for deeply redundant features or features that can be functional in a contingent context. So the genetic load arguments cannot be used to definitively say large parts of the genome are functionless, it can only say large parts could not evolve and maintain function via natural selection.

    Genetic load arguments don't preclude evolution by another mechanism like say an astronomically remote improbable event indistinguishable from a miracle (which is pretty much Koonin's solution to OOL, or for that matter the creationist solution to life's major features).

    Though I'd agree with you spurious RNA transcripts are not direct evidence of function, the fact specific DNA regions are targeted for methylation markings and that those methylation markings seem important for proper function, it's too early to say there is no role for those sections of DNA even supposing some of the transcription of those regions is spurious. NIH ROADMAP has only scratched the surface of tracking the "methylome" that is imprinted on "junk" DNA.

    By the way, thanks for backing my citation of Hermann Muller on mutational load. You're most certainly right to say selection mechanisms can't evolve nor maintain large amount of function in the genome, and if the medical researchers of ENCODE and ROADMAP discover evidence of function, that is evidence of functionality that cannot come about and be maintained by Darwinian means because of the mutational load problem.

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    1. With Piotr's observant comment above in mind, I have some questions for Sal ("liarsfordarwin") and others who argue against the concept and evidence of 'junk DNA':

      If, instead of a (or the) human genome, the focus of a discussion/debate were on the genomes of Necturus maculosus, Lilium longiflorum, Protopterus aethiopicus, Amoeba dubia, and/or Allium cepa, would you be as determined to argue against the concept and evidence of 'junk' DNA, and would the gist or wording of your arguments be the same (i.e. rely on the same premises)?

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    2. "Yes we can if the functions are deeply redundant, which indeed they are"

      What functions are those, and how do you know they are "deeply redundant"?

      Nobody is impressed by this kind of ad-hoc reationalization. You need to bring actual evidence. "Was methylated once in some tissue" isn't evidence that is "deeply redundantly functional" whatever the fuck that even means.

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    3. "remote improbable event indistinguishable from a miracle (which is pretty much Koonin's solution to OOL"

      No it isn't, you are misrepresenting Eugene Koonin. He merely published a paper to suggest one kind of solution in the multiverse, he isn't saying that is the only sensible option or even that it's what he believes.

      You nutbags have been mistakenly obsessed with that paper ever since it's publication.

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    4. "Yes we can if the functions are deeply redundant, which indeed they are, and also if mutations are not completely random but are restricted to avoid damaging function. "

      Numbers please - tossing out these vague assertions and expecting your point to be settled would be like, oh I don't know - pointing out how your pal Wells distorted quotes in his book to misrepresent concepts and declaring that all creationists are dishonest and/or incompetent without offering any additional support and expecting you to just accept that as fact.

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  5. and also if mutations are not completely random but are restricted to avoid damaging function

    Right, that's why we can't get cancer - oh, wait....

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