Wednesday, October 11, 2017

Historical evolution is determined by chance events

Modern evolutionary theory is based on the idea that alleles become fixed in a population over time. They can be fixed by natural selection if they confer selective advantage or they can be fixed by random genetic drift if they are nearly neutral or slightly deleterious [Learning about modern evolutionary theory: the drift-barrier hypothesis]. Alleles arise by mutation and the path that a population follows over time depends on the timing of mutations [Mutation-Driven Evolution]. That's largely a chance event.

As a result, the history of evolution is much more unpredictable than most people realize, especially when coupled with environmental effects. I call this "Evolution by Accident." It's similar to Stephen Jay Gould's idea of contingency.

The idea has been around for a very long time but recently it has become possible to test the idea at the molecular level by looking at actual mutations occurring in evolving populations [Strolling around slopes and valleys in the adaptive landscape]. It's also possible to reverse engineer an ancient gene and then test to see which of the historical mutations were important. This is what Joseph Thornton's group did with vertebrate glucocorticoid receptor (GR) genes. They showed that historical contingency and chance events dominated the evolutionary pathway leading to a cortisol-specific version of these receptors genes (Harms and Thornton, 2014). [see Historical contingency and the evolution of the glucocorticoid receptor].

Now Thornton's group has provided further evidence of historical contingency by looking at the evolution of steroid hormone receptor genes (Starr et al., 2017). Steroid hormone receptor proteins normally don't bind specifically to DNA but in the presence of hormone they form a hormone-protein complex that binds to specific sequences near the promoters of some genes. This promotes transcription of those genes. The receptor proteins are transcription activators in the presence of hormone.

There are two related steroid hormone receptor genes in vertebrates. One of them responds specifically to corticosteroids, androgens, and progesterones by binding to the steroid response element (SRE) with the sequence AGAACA. The other responds to estrogen by binding the estrogen response element (ERE) with the sequence AGGTCA. The genes apparently arose by gene duplication from an ancestral gene. Thornton's group reconstructed the ancestral gene (AncGR1) and showed that it binds to ERE.

Following an ancient gene duplication, one of the duplicated genes shifted function to become responsive to corticosteroids by binding to a different sequence (SRE). The shift in binding specificity is due to three substitutions in the DNA-binding site, or recognition helix (RH). However when these three mutations are added to the hypothetical ancestral protein, they are not sufficient to convert the receptor into a fully functional receptor that recognizes corticosteroids and binds tightly to SRE. Eleven different amino acid substitutions were also required during the evolution of the new receptor protein. These eleven substitutions were "permissive" in the sense they prepared the way for the shift in hormone recognition and DNA binding.

Thus, the evolution of the new receptor gene involved 11 permissive mutations (11P) followed by 3 RH mutations. We want to know how many different pathways could have produced the same result. Is the gene we see today the only possible outcome of millions of years of evolution or is it only one of many possibilities in sequence space?

Starr et al. (2017) began by constructing an ancestral gene containing the eleven permissive mutations (AncGR1 + 11P). They then asked how many pathways could lead to a change in sequence specificity. They answered the question by making mutation in four codons of the recognition helix—the three that were actually observed and one other that was bound to be important. They substituted all 20 amino acids at each of the four sites creating 160,000 combinations. They found 828 new variants that were just as good or better than the current mammalian gene. There were another 500 variants that were functional but not as efficient as the current gene.

What this means is that there are more than one thousand different ways of evolving a new receptor that recognizes the sequence AGAACA instead of AGGTCA. Almost all of the functional variants are accessible by gradual step-wise mutation of the three or four codons without going through a nonfunctional intermediate. The authors conclude that the historical outcome is not unique— it's only one of many possibilities. Some of these possibilities involved shorter paths than the historical outcome.
Taken together, these data indicate that the historical trajectory was not the only path, or even the shortest, from the ancestral RH to a derived protein that is SRE-specific.
This is not surprising. There's tons of data pointing to the same conclusion. In addition, evolutionary theory has always assumed that chance and contingency play an important role in the history of life. What's important about this paper is that the authors have quantified functional sequence space by testing all possible outcomes.

The pathway to SRE binding is enhanced by the eleven permissive mutations that preceded the change in binding. There are some pathways to SRE binding that don't require those permissive mutations but most do. The 11P mutations are mostly neutral and they presumably arose by chance during the evolution of these receptor genes. That means there are two different roles for chance and contingency in the evolution of corticosteroid-responsive receptors. Here's how the authors express it ...
Our results shed light on the roles of determinism and chance in protein evolution. The primary deterministic force is natural selection, which drives the evolution of forms that optimize fitness. Chance appears in two non-exclusive ways: as historical contingency, when the accessibility of some outcome depends on prior events that cannot be driven by selection for that outcome; and as stochasticity, when there are paths to numerous possible genotypes of similar function, and which one is realized is random.
Keep in mind that we are dealing with the evolution of a corticosteroid-responsive receptor. There's no particular reason why this particular receptor evolved as opposed to one that responded to other chemicals in the body and there's no particular reason why the new receptor had to bind to AGAACA as opposed to some other sequence variant. Therefore, the possible pathways to evolution of a new functional gene are many times greater than this result indicates.


Harms, M.J., and Thornton, J.W. (2014) Historical contingency and its biophysical basis in glucocorticoid receptor evolution. Nature, 512:203. [doi: 10.1038/nature13410]

Starr, T.N., Picton, L.K., and Thornton, J.W. (2017) Alternative evolutionary histories in the sequence space of an ancient protein. Nature, 549:409-413. [doi: 10.1038/nature23902]

15 comments :

  1. There's no particular reason why this particular receptor evolved as opposed to one that responded to other chemicals in the body and there's no particular reason why the new receptor had to bind to AGAACA as opposed to some other sequence variant. Therefore, the possible pathways to evolution of a new functional gene are many times greater than this result indicates.

    Life can walk, swim or fly; breathe oxygen, carbon dioxide or hydrogen sulfide.... So it shouldn't be surprising that it's "turtles all the way down" (I mean that in a good way).

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  2. The fact that there is such a diversity of life "out there" (hundreds of thousands of species of beetles alone) is evidence of the many possible evolutionary trajectories. And given the still limited time that life has existed on this planet, there is probably even more unsampled but possible variation in forms.

    Any particular system or molecule we see is likely to be just one among basically countless possible, but coincidentally never sampled and therefore unrealized biochemical pathways.

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    1. @Mikkel

      The fact that there is such a diversity of life "out there" (hundreds of thousands of species of beetles alone) is evidence of the many possible evolutionary trajectories

      Beetles are still beetles...just as homo sapience are still homosapience...billions of variations...

      Would it be kind of boring in everyone man on earth looked like you? And every women would look like your wife? That is if you have one... ;-)

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    2. You seem to have missed the point, which is just that there are many different ways evolution could have turned out, but didn't, in large part due to historical chance events.

      Whether something is "boring" is not a valid excuse for accepting or rejecting it's possibility. The facts of the matter are not determined by how they feel to you.

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  3. Two points.
    First having evolution by random fixing of all alleles , and that by chance, surely makes evolution too chancy as a option for biology origins.
    Selection on a mutation is bad enough. BUT mutations affecting a population without selection is a dramatic OTHER OPTION as proposed by darwin.
    Something wrong here.

    second point.
    Is it being said here a population will evolve without selection going on?
    That alleles will go through a population, just random, and change body plans?
    Recently i was shocked to hear professional evolutionist say populations are always evolving.
    The whole point of puncuiated equilbrium was that THEY DIDN'T evolve. instead only segregated pairs, geographically probably, evolved quickly and then they replaced the parent population by them going extinct or somehow.
    PE means populations don't evolve, and the fossil record proves they didn't, by the whole group. Is random alleles trying to reject PE?
    Anyways it must be people/animals today are not evolving.
    If so how??

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  4. I wonder whether Larry is not giving the wrong impression by the title of this post. He is, I think, not saying that natural selection plays no role in the outcome, only that "chance" initial steps, the first mutations, can lead to process to follow different paths.

    But most of the movement along those paths leads to adaptation, owing to natural selection.

    Or do I misunderstand?

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    1. Joe, I thought the part of Larry's post I quoted above, and this quote from the paper, lay out the fact that those "'chance' initial steps" can be quite a substantial part of the total path (recall the 11 "permissive" steps, before we even think of Larry's final point that evolution of a corticosteroid-responsive receptor, as opposed to one responsive to another chemical, was contingent in itself):

      Chance appears in two non-exclusive ways: as historical contingency, when the accessibility of some outcome depends on prior events that cannot be driven by selection for that outcome; and as stochasticity, when there are paths to numerous possible genotypes of similar function, and which one is realized is random.

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    2. The issue is whether the function is the accidental result of random wandering in protein space to an arbitrary place. Or is the wandering biased by natural selection toward regions having some function? Many readers who see the phrase "determined by chance events" will take it to mean the former.

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    3. It seems to me the specific function is not the only outcome being investigated here. It is also the particular protein that performs that function. If more than one protein can perform the same function more or less equivalently, then even if the function was an inevitable outcome of evolution, the specific protein that arises would not be.

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    4. Right, even if "prior events...cannot be driven by selection for that outcome," this doesn't necessarily mean they weren't "biased by natural selection toward regions having some function."

      I'm certainly not equipped to deal with such a question on a general basis, so I'll ask specifically with regard to the steps that were outlined in this paper: Is it at all possible to know (or at least to arrive at a reasonable surmise) which of these were "biased by natural selection toward regions having some function"?

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  5. I thought the point of this and other work was that relatively small changes can predispose a lineage to take a certain evolutionary path. A small change in sex-determination in an ancestral solitary insect species can lead them on the inevitable path to becoming social - ants and bees. Some minor non-selected change in ATPase or some other protein billions of years ago that was on a path to allow ATP being produced from mechanical work would have led to an utterly different biosphere today.

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    1. It can't merely be PREDISPOSE. Evolutionism was based on populations changing because they had tpo TO survive.
      selection must mean something and have selected some gain to survival/fitness.
      it can't be gradual changes without a selective advantage.
      This undercuts the whole evolutionary claim surely.

      A lineage/population will only have new body plans and these change and change, as evolutionism needs, if the need is great.
      Populations di not evolve as a natural thing.
      People are not evolving today.
      Evolutionists should be clear about this.

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    2. "Evolutionism is based on populations change because they had to TO survive." Well, not really. Populations change. If they have traits that fit their environment well, they survive. If they don't, they die out. Extinction is always an option.

      Evolution doesn't "need" anything.

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    3. It does need something. Evolution is a process, your side claims, changing body plans. So small matter.
      The environment must FIRST change and some of the parent population, to survive in the new one, must have NEW traits that allow it to survive and so a new population THAT HAS EVOLVED.

      Populations going from a fish to a rhino need good reasons for body plan changes.
      Science fiction is wrong. people are not evolving right now in any direction to bigger heads etc. we are in stasis. As PE would preach it.

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  6. I wish that we could (1) translate this into causal language and (2) get the history right. "Chance" and "contingency" (and "constraints") are not causes. These are explanatory devices, whose meaning depends on the counterfactual idea of evolution without chance or contingency. Rather than making positive claim about causation, they refer back to an ideal. This is why it is so jarring to say that the course of evolution is "determined" by chance. Can we have a different theory of evolution, instead of Darwinism-plus-excuses-for-its-failure-to-apply?

    The claim that "evolutionary theory has always assumed that chance and contingency play an important role in the history of life" is dubious. Our thinking has changed so much since the molecular revolution that people forget the pre-molecular view in which evolution was a deterministic process of shifting gene frequencies to a new optimum determined by the environment.

    In his 1975 book, Maynard Smith gives a very close retelling of King's 1971 argument that the correlation of amino acid frequencies with codon numbers (in the genetic code) can be reconciled with selective allele fixations, and does not require neutrality, as argued earlier by King and Jukes in 1969. King was thinking in the new way, invoking mutation-driven evolution. Maynard Smith concludes by saying:

    "Hence the correlation does not enable us to decide between the two. However, it is worth remembering that if we accept the selectionist view that most substitutions are selective, we cannot at the same time assume that there is a unique deterministic course for evolution. Instead, we must assume that there are alternative ways in which a protein can evolve, the actual path taken depending on chance events. This seems to be the minimum concession the selectionists will have to make to the neutralists; they may have to concede much more."

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