Monday, June 24, 2013

Laurence Hurst Discusses Junk DNA

Laurence Hurst is a Professor of Evolutionary Genetics in the Department of Biology and Biochemistry at The University of Bath (United Kingdom). He did his graduate studies under W.D. Hamilton at Oxford so it's safe to assume that he has adaptationist leanings.

Hurst wrote a comment in BMC Biology where he criticized the logic employed by those of us involved in the junk DNA debate [Open questions: A logic (or lack thereof) of genome organization]. Here's part of what Hurst says about logic ...
As a graduate student I was advised that if you don’t understand why an animal does what at first sight looks like behavior contrary to its best interests, then you should presume that it is you, not the animal, that is stupid. Look harder, the wisdom goes, and you will discover natural selection’s cunning logic.
That's bad advice, as Stephen Jay Gould and Richard Lewontin pointed out 35 years ago [The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme]. But, like many adaptationists, Hurst is willing to concede that this kind of reasoning may not apply at the molecular level.
While this may be good advice to those studying organismic behavior or anatomy, when we approach genomic anatomy and behavior it will not do.

Indeed, typically when thinking about genomes people often make the opposite presumption. Intergenic DNA was dismissed as irrelevant junk and many transcripts are presumed to be just so much noise. Synonymous mutations have been assumed to be neutrally evolving and where in a genome a gene sits is considered to be largely irrelevant. But are these assumptions more witness to a lack of understanding rather than robust statements about how genomes function and evolve? You are, after all, alive reading this, testament to the fact that your genome is doing something right.

So then, what features of our and other genomes are functionally relevant and which just so much noise? More importantly, when selection does act, why is it acting?
Hurst seems to be assuming that we know nothing about most of the genome and he makes the erroneous assumption that junk DNA advocates dismiss all intergenic DNA as junk. These are the hallmarks of someone who is uniformed about the debate over junk DNA. There is strong positive evidence for junk and those arguments need to be addressed (e.g. genetic load, C-Value Paradox). There is also strong evidence for functional intergenic sequences (origins, centromeres. telomeres, SARs, regulatory regions, etc.) and that evidence is part of the debate. None of the advocates of junk DNA claim that all intergenic DNA is junk.

We know that half of our genome is composed of bits and pieces of defective transposons. That's not ignorance. Broken genes are ... broken genes. They don't work. They are junk. We know enough about genes to recognize the difference between active functional transposons and those that carry lethal mutations of are missing large pieces of their coding region. It's logical to conclude that about half of our genome is junk based on those facts alone.

We know enough about transcription to know that spurious transcription and production of junk RNA transcripts are an inevitable consequence of the basic biochemistry of DNA binding proteins. That's not ignorance.

We know enough about nearly neutral mutations and molecular evolution to know the the existence of an approximate molecular clock means that most synonymous mutations and amino acid substitutions are fixed by random genetic drift. That's not due to a lack of understanding. Hurst has published evidence that some of these seemingly neutral mutations affect function but he ignores the evidence that most behave as if they were neutral.

The fact that you are alive does, indeed, mean that your genome is doing something right. It's good enough for survival of our species. It does not mean that all of your genome is functional.

To his credit, Hurst recognizes that the ENCODE scientists were wrong and that the null hypothesis is NOT natural selection.
The challenge is difficult. Assuming that sites involved in interactions are all functional isn’t good enough. By this, the logic employed by ENCODE, following a collision between a car and a pedestrian, a car’s bonnet would be ascribed the 'function' of projecting a pedestrian many meters and the pedestrian would have the 'function' of deforming the car’s bonnet. Similarly, we expect, for example, accidental transcription factor-DNA binding to go on at some rate, so assuming that transcription equals function is not good enough. The null hypothesis after all is that most transcription is spurious and alternative transcripts are a consequence of error-prone splicing. Conversely, assuming unbound sequence, such as nucleosome-free regions, to be lacking in function can mislead, as they can be critical for the proper control of gene expression.
I get the feeling that Hurst is uncomfortable with the idea that most of our genome is junk [see Hacking the Genome] but he's at least on the right track when he recognizes that there's still a legitimate scientific debate.


Hat Tip: Dan Graur: Laurence Hurst’s Error: The Inability to Distinguish between a Stupid Animal, a Dead Animal, and the Elephant in the Room

4 comments :

  1. I apologize for accidentally closing comments on this post. Commenting is now allowed.

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  2. "the existence of an approximate molecular clock means that most synonymous mutations and amino acid substitutions are fixed by random genetic drift"

    Interestingly, this is not at all what Zuckerkanl and Pauling had in mind when they introduced the molecular clock hypothesis in 1965 ( http://rana.lbl.gov/290/papers/zuckerkandl_pauling.pdf ). Instead, they seem to have been assuming that most observed changes were fixed under positive selection, but made a distinction between the evolution of sequences which are far from optimality (which they did not expect to be clock-like, e.g. a new function for a particular gene might appear in a particular lineage, causing accelerated evolution of that gene in that lineage), and that of sequences which are nearly optimal but tracking a gradually changing fitness landscape (which they did expect to be clock-like, on the assumption that such fitness landscape changes happen more or less continuously in all lineages).

    "Hurst has published evidence that some of these seemingly neutral mutations affect function"

    Independently of Hurst's work, the evidence from model-based approaches ( e.g. http://www.ncbi.nlm.nih.gov/pubmed/16107593 and http://www.virologyj.com/content/5/1/160 ) clearly shows that site-to-site variation of synonymous substitution rates is pervasive. The scale of variation is much too fine to be explained by mutation rate variation - instead, this is indicative of weak purifying selection. Hurst has described several plausible mechanisms for this.

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    Replies
    1. Typo - that should be "Zuckerkandl". I should also point out that they did mention (but chose not to emphasize) genetic drift in their paper.

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  3. The creationists on UD are in a true conondrum here, do they side with an actual true "Darwinist"(read, adaptationist) and say he has it right, or reject both junk-DNA and the adaptationist arguments against it?

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