Stepwise evolutionary pathways to highly specific protein binding partners. That seems imposs--

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The context here is a protein-evolution scenario that seems to be near a frontier of accessibility via standard Darwinian mechanisms. They’re called orthogonal binders defined this way in the abstract of a new paper in Cell Systems: “Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs.”

This seems a candy store for (say) a scientifically-trained person engaged in (and paid for) motivated reasoning and safely insulated from the scientific literature. After all, it is (IMO) hard to imagine–at first blush–how two proteins could evolve, together, to bind each other with such high specificity that their close relatives are excluded from the conversation. It gets comically worse when/if we trot out a scenario in which the partners would need nearly 20 mutations to get to their happy place, and we can make the whole thing seem literally impossible by stipulating that every step in the trajectory has to result in a fitness increase. Yo, evolution, let’s see you do that!

Evolution: :man_shrugging: Okay!

Abstract:

Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if they exhibit sufficient affinity. Until now, finding a fully functional single-mutation path connecting orthogonal pairs could only be achieved by full enumeration of intermediates and was restricted to pairs that were mutationally close. We present a computational framework for discovering single-mutation paths with low molecular strain and apply it to two orthogonal bacterial endonuclease-immunity pairs separated by 17 interfacial mutations. By including mutations that bridge identities that could not be exchanged by single-nucleotide mutations, we discovered a strain-free 19-mutation path that was fully functional in vivo. The change in binding preference occurred remarkably abruptly, resulting from only one radical mutation in each partner. Furthermore, each of the specificity-switch mutations increased fitness, demonstrating that functional divergence could be driven by positive Darwinian selection.

Here’s a great paragraph from their Discussion (the paragraph before it is also excellent and clear):

A key question in the evolution of orthogonal binding pairs is how ultrahigh specificity evolves by a single-mutation trajectory without crossing a fitness valley. Our results provide a case-study in which each of the specificity-switching mutations are not only tolerated but may endow their host with a selective advantage relative to the parental population due to functional asymmetry in the interacting pair, as in a toxin-antitoxin system. This polarizes the function-altering evolutionary process, increasing the likelihood of selecting a long series of mutations, whereas the reverse mutations are counter selected. In other words, the functional asymmetry in the toxin-antitoxin system suggests preferred directions for the evolutionary process depending on specific environmental conditions.

They make the main caveat clear:

An important question that is left unanswered by our study is how general the observations we made here are to the emergence of novel protein-protein interactions. Only very few previous studies reconstructed mutational trajectories at the single-mutation level, and unlike our results, they demonstrated multiple paths that go through generalist or promiscuous intermediates that bind both extant partners. The abruptness of the functional transition that we observe may be due to the properties of colicin endonuclease/Im pairs, including high specificity barriers, high affinity, and functional asymmetry. Although these properties are extreme in colicins, we hypothesize that they are not unique to them or even to toxin/antitoxin systems and that they are likely to be typical of high-affinity and -specificity receptor/ligand systems where functional insulation is essential.

Evolution is easy, my friends.

Paper is open access, even in Seattle:
https://www.cell.com/cell-systems/fulltext/S2405-4712(25)00095-X

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Evolution says, “Hold my beer!” :clinking_beer_mugs:

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Michael Behe: [nervously sweating and silently grumbling]

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Wishful thinking!

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This is not what the story of HCQ resistance in Malaria nor Lenski’s LTEE experiments are telling us, not at all.

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Are you accusing these scientists of lying about what they observed in their lab?

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No single example or experiment really tells us broadly about evolution. That’s as much of a problem for both creationists or evolutionists aiming to extrapolate from such individual cases to broad patterns of evolution.

It is definitely the case that some things are more difficult to evolve than others, and that the environment and selective schemes, and the genetic background of the organisms, all matter with respect to how easily any particular thing evolves.
Just to pick an example the Cit+ phenotype evolved more easily in Scott Minnich’s experiment because they employed a different selection scheme that much more strongly rewarded intermediate mutations. Weirdly creationists have been trying to spin that result as incomprehensibly being a problem for evolution. Which literally doesn’t make logical sense.

Another interesting example experiment that seems to defy a lot of recent creationist rhetoric about “reductive evolution”, is from the Ratcliffe lab where they’re working on experimentally evolving multicellularity. They have found the curious result that selecting for increased organismal size has favored and stabilized whole genome duplication in all replicate cell lines in the experiment:

Abstract

Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution1,2,3,4. However, given the instability of newly formed polyploid genomes5,6,7, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Here, using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE)8, we show that diploid snowflake yeast (Saccharomyces cerevisiae) under selection for larger multicellular size rapidly evolve to be tetraploid. From their origin within the first 50 days of the experiment, tetraploids persisted for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in 10 replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modelling and counter-selection, we found that tetraploidy evolved because it confers immediate fitness benefits under this selection, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, having a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection and fuel long-term innovations by creating additional dimensions of heritable genetic variation.

The cells now have double the genome size than when the experiment began. Population genetics implies that this expanded genome must be under more relaxed selection, possibly facilitating more constructive neutral evolution going forward. It will be very interesting seeing what comes of this experiment in the future.

Other curious products of this experiment already, is that the multicellular colonies have evolved massively increased toughness:

We are currently running a Lenski-inspired Multicellularity Long Term Evolution Experiment (MuLTEE), which we hope will continue for at least the next 25 years. So far, we have currently put snowflake yeast through >1,000 rounds (~5000 generations) of selection for larger group size, evolving multicellular yeast that are ~20,000 times larger than their ancestor. These individual snowflake yeast remain clonal and are visible to the naked eye (larger than fruit flies). They have accomplished this feat through sustained biophysical adaptation, evolving far more elongated cells that ‘entangle’, increasing their mechanical toughness by over 10,000-fold. Individual snowflake yeast evolve from being weaker than gelatin, to as strong and tough as wood. You can read more about this work here. In this system, we are investigating the genomic causes and consequences of multicellular evolution, the origin of multicellular development, emergent fluid flows, and are examining how multicellularity becomes entrenched, preventing reversion (see current projects).

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No, not at all. I was replying to @Nesslig20 post at 3.

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Oh, OK. I think you are probably right. Behe has nothing to worry about, since his fans and followers are completely incapable of understanding scientific evidence. For example, when a paper was published on the evolution of choloroquine resistance in malaria that completely refuted his claims in The Edge of Evolution, Behe brazenly lied about this and said it was actually a vindication for him! And, even more incredibly, most of his followers simply believed him.

A Key Inference of The Edge of Evolution Has Now Been Experimentally Confirmed | Evolution News and Science Today