A Surprisingly Simple Biochemistry Rule Drives the Evolution of Useless Complexity

Biochemical Concept

New study shows that proteins become biochemically addicted to complex interactions without adaptation.

A new study at the University of Chicago has shown that elaborate protein structures accumulate over deep time even when they serve no purpose, because a universal biochemical property and the genetic code force natural selection to preserve them. The work was published on December 9, 2020, in Nature.

Most proteins in our cells form specific complexes with other proteins, a process called multimerization. Like other kinds of complexity in biology, multimers are usually thought to persist over evolutionary time because they confer some functional benefit that is favored by natural selection.

“How complexity evolves is one of the great questions of evolutionary biology,” said senior author Joseph Thornton, PhD, professor of human genetics and ecology and evolution at the University of Chicago. “The classic explanation is that elaborate structures must exist because they confer some functional benefit on the organism, so natural selection drives ever-increasing states of complexity. Clearly, in some cases, complexity is adaptive, like the evolution of the eye: complex eyes see better than simple ones. But at the molecular level, we found that there are other simple mechanisms that drive the build-up of complexity.”

The research team, led by Thornton and University of Chicago postdoctoral fellow Georg Hochberg, PhD, set out to study the evolution of multimerization in a family of proteins called steroid hormone receptors, which assemble into pairs (called dimers).

They used a technique called ancestral protein reconstruction, a kind of molecular “time travel,” Thornton said, that allowed them to recreate ancient proteins in the lab and experimentally examine how they were affected by mutations that happened hundreds of millions of years ago.

To their surprise, they found that the ancient proteins functioned no differently when assembled into a dimer than if they had never evolved to dimerize at all. There was nothing useful or beneficial about forming the complex.

The explanation for why the dimeric form of the receptor has persisted for 450 million years turned out to be surprisingly simple. “These proteins gradually became addicted to their interaction, even though there is nothing useful about it,” explained Hochberg, who is now a group leader at the Max Planck Institute in Marburg, Germany. “The parts of the protein that form the interface where the partners bind each other accumulated mutations that were tolerable after the dimer evolved, but would have been deleterious in the solo state. This made the protein totally dependent on the dimeric form, and it could no longer go back. Useless complexity became entrenched, essentially forever.”

The researchers showed that simple biochemical, genetic, and evolutionary principles make entrenchment of molecular complexes inevitable. The genes that code for every protein are subject to a constant hail of mutations over generations, many of which would disrupt the protein’s ability to fold up and function properly. A form of natural selection called purifying selection removes these deleterious mutations from the population.

Once a protein evolves to multimerize, the parts that form the interface can accumulate mutations that would be deleterious if the protein were in the solo state, so long as they can be tolerated in the multimer. Purifying selection then entrenches the complex form, preventing a return to the solo state.

The researchers showed that a simple and universal rule of biochemistry underlies entrenchment. Proteins are made up of amino acids, which may be water-soluble, or hydrophobic, meaning they dissolve easily in oil but not water. Usually, proteins fold so the water-soluble amino acids are on the outside and the hydrophobic amino acids are on the inside. Mutations that make a protein’s surface more oil soluble impair its folding, so purifying selection removes them if they occur in solo proteins.

If the protein evolves to multimerize, however, those hydrophobic amino acids on the interface surface are hidden from water, and become invisible to purifying selection. The multimer is then entrenched, because returning to the solo state would expose the now-oil-soluble and deleterious interface.

This “hydrophobic ratchet” appears to be universal. The researchers analyzed a massive database of protein structures, including hundreds of dimers and related solo proteins, and found that the vast majority of interfaces have become so hydrophobic that the dimeric form is deeply entrenched.

This mechanism, operating on thousands of proteins over hundreds of millions of years, could drive the gradual accumulation of many useless complexes inside cells.

“Some complexes surely have important functions, but even those will be entrenched by the hydrophobic ratchet, making them harder to lose than they would otherwise be,” Hochberg said. “With the ratchet constantly operating in the background, our cells have probably built up a massive stock of entrenched complexes, many of which never performed a useful function, or long ago ceased to do so.”

Future directions include investigating whether or not interactions other than multimerization may be the result of entrenchment. “This was a story about proteins dimerizing with other copies of themselves, which is a super common process,” said Thornton. “But there are lots of other interactions in cells, and we think it’s possible that some of those may have accumulated during evolution because of a similar kind of acquired dependence on molecular complexity.”

Reference: “A hydrophobic ratchet entrenches molecular complexes” by Georg K. A. Hochberg, Yang Liu, Erik G. Marklund, Brian P. H. Metzger, Arthur Laganowsky and Joseph W. Thornton, 9 December 2020, Nature.
DOI: 10.1038/s41586-020-3021-2

The study, “A hydrophobic ratchet entrenches molecular complexes,” was supported by a Chicago Fellowship and the National Institutes of Health (R01GM131128 and R01GM121931). Additional authors include Brian P.H. Metzger of the University of Chicago, Yang Liu and Arthur Laganowsky of Texas A&M University, and Erik G. Marklund of Uppsala University.

13 Comments on "A Surprisingly Simple Biochemistry Rule Drives the Evolution of Useless Complexity"

  1. The dimerization is not useless if it acts to protect the protein from being rendered nonfunctional by hydrophobic mutations! Based on this article it confers protection against defects that would render the protein useless and thus it confers a “Natural Selection” advantage. It would only be useless in a universe where Life was intelligently designed. Furthermore, useful complexity would be far less likely to arise spontaneously without this property preserving complexities before they are useful.

    • Torbjörn Larsson | December 26, 2020 at 1:02 pm | Reply

      Interesting question! And an irony that the next comment was precisely such a mindless creationist comment that you pointed out is rejected by observation – superstitious people really don’t care about who read their wretched magic ablutions, do they!? I think comedian Jimmy Carr put it something like: “Believers in the made up will get their reward in the made up. Good luck with that!”

      But I don’t think that these scientists are saying their case is general – before I read your comment, I posted one with an example of where a lock in mechanism isn’t strictly necessary but the dimer is rare likely because the monomer suffice.

      Here they found a specific counterexample to “must have protective selective advantage” where complexity may have been a consequence of how general proteins are self folding with few dedicated enzymes doing it but a host that detect and unfold wrongly folded. It is itself likely an evolutionary “locked in” function from early evolution, but they show it can have further consequences under near neutral drift (too weak selection to make a difference).

      I am vary of universal claims in biology (” essentially forever”), which has lots of mechanisms and varied outcome and consequently very few laws. Similar mechanisms abound in eukaryotes, where ribosomes have become large protein complexes and genomes riddled with genetic parasites such as transposons, yet we can see that parasites evolves small ribozomes (e.g. the parasitic fungi Microsporidia) and animals may evolve genomes with little transposons (e.g. the pufferfish). I’m pretty sure we can or could see the same in multimers, see my example or it could evolve by horisontal gene transfer from other species with possibly useful monomers.

      If evolution results in complexity, it is a rarefied result. Most populations are unicellular organisms with relatively few genes (bacteria, archaea), and most complex animals are parasites with more complex lifestyles but correspondingly much simplified body plans.

  2. Babu G. Ranganathan | December 25, 2020 at 7:28 am | Reply

    Babu G. Ranganathan*
    (B.A. Bible/Biology)


    ONLY LIMITED EVOLUTION (micro-evolution or evolution within biological “kinds”) is genetically possible (such as the varieties of dogs, cats, horses, cows, etc.), but not macro-evolution, or evolution across biological “kinds,” (such as from sea sponge to human). All real evolution in nature is simply the expression, over time, of already existing genes or variations of already existing genes. For example, we have breeds of dogs today that we didn’t have a few hundred years ago. The genes for these breeds had always existed in the dog population but never had opportunity before to be expressed. Only limited evolution, variations of already existing genes and traits, is possible.

    The genes (chemical instructions or code) for a trait must first exist or otherwise the trait cannot come into existence. Genes instruct the body to build our tissues and organs. Nature is mindless and has no ability to design and program entirely new genes for entirely new traits.

    Evolutionists believe that, if given millions of years, accidents in the genetic code of species caused by the environment will generate entirely new code making evolution possible from one type of life to another. It’s much like believing that by randomly changing the sequence of letters in a romance novel, over millions of years, can turn the novel into a book on astronomy! Not to worry. We’ll address the issue of “Junk DNA” in a moment.

    WHAT ABOUT NATURAL SELECTION? Natural selection doesn’t produce biological traits or variations. It can only “select” from biological variations that are possible and which have survival value.

    HOW COULD SPECIES HAVE SURVIVED if their vital tissues, organs, reproductive systems, etc. were still evolving? A partially evolved trait or organ that is not complete and fully integrated and functioning from the start would be a liability to a species, not a survival asset. Plants and animals in the process of macro-evolution would be unfit for survival. For example, “if a leg of a reptile were to evolve (over supposedly millions of years) into a wing of a bird, it would become a bad leg long before it became a good wing” (Dr. Walt Brown, scientist and creationist). Survival of the fittest actually would have prevented evolution across biological kinds!

    NEW SPECIES BUT NOT NEW DNA: Although it’s been observed that new species have come into existence, they don’t carry any new genes. They’ve become new species only because they can’t be crossed back with the original parent stock for various biological reasons. A biological “kind” allows for new species but not new genes. Nature has no ability to invent new genes for new traits. Only limited variations and adaptations are possible in nature, and all strictly within a biological “kind” (i.e. varieties of dogs, cats, etc.).

    Dr. Randy J. Guliuzza’s extensive research points to a better explanation than natural selection for variation and adaptation in nature. Dr. Guliuzza explains that species have pre-engineered mechanisms that enable organisms to continuously track and respond to environmental changes with system elements that correspond to human-designed tracking systems. This model is called CET (continuous environmental tracking). His research strongly indicates that living things have been pre-engineered to produce the right adaptations and changes required to live in changing environments. It’s much like a car that’s been pre-engineered so that the head lights turn on automatically when day changes to night.

    What about genetic and biological similarities between species? Genetic information, like other forms of information, cannot happen by chance, so it is more logical to believe that genetic and biological similarities between all forms of life are due to a common Designer who designed similar functions for similar purposes. It doesn’t mean all forms of life are biologically related! Only genetic similarities within a natural species proves relationship because it’s only within a natural species that members can interbreed and reproduce.

    Many people have wrong ideas of how evolution is supposed to work. Physical traits and characteristics are determined and passed on by genes – not by what happens to our body parts. For example, if a woman were to lose her finger this wouldn’t affect how many fingers her baby will have. Changing the color and texture of your hair will not affect the color and texture of your children’s hair. So, even if an ape or ape-like creature’s muscles and bones changed so that it could walk upright it still would not be able to pass on this trait to its offspring. Only changes or mutations that occur in the genetic code of reproductive cells (i.e. sperm and egg) can be passed on to offspring.

    What about the new science of epigenetics? Epigenetics involves inheritable factors which can turn already-existing genes on, but epigenetics doesn’t create new genes.

    Most biological variations are from new combinations of already existing genes, not mutations. Mutations are accidents in the genetic code caused by nature (i.e. environmental radiation), are mostly harmful, and have no capability of producing greater complexity in the code. Even if a good accident occurred, for every good one there would be hundreds of harmful ones with the net result, over time, being harmful, even lethal, to the species. Even if a single mutation is not immediately harmful, the accumulation of mutations over time will be harmful to the species resulting in extinction. At very best, mutations only produce further variations within a natural species.

    All species of plants and animals in the fossil record are found complete, fully formed, and fully functional. This is powerful evidence that all species came into existence as complete and fully formed from the beginning. This is only possible by creation.

    God began with a perfect and harmonious creation. Even all the animals were vegetarian (Genesis 1:30) in the beginning and did not struggle for survival nor kill and devour each other. Macro-evolutionary theory does not begin with a perfect and harmonious creation as the Bible states. The Bible and macro-evolutionary theory cannot both be true.

    All the fossils that have been used to support human evolution have been found to be either hoaxes, non-human, or human, but not non-human and human (i.e. Neanderthal Man was discovered later to be fully human).

    There has never been unanimous agreement among evolutionary scientists on ANY fossil evidence that has been used to support human evolution over the many years, Including LUCY.

    The actual similarity between ape and human DNA is between 70-87% not 99.8% as commonly believed. The original research stating 99.8% similarity was based on ignoring contradicting evidence. Only a certain segment of DNA between apes and humans was compared, not the entire DNA genome.

    Also, so-called “Junk DNA” isn’t junk. Although these “non-coding” segments of DNA don’t code for proteins, they have recently been found to be vital in regulating gene expression (i.e. when, where, and how genes are expressed, so they’re not “junk”). Also, there is evidence that, in certain situations, they can code for protein.

    ARE FOSSILS REALLY MILLIONS OF YEARS OLD? (Internet article by author)

    Visit my latest Internet site: THE SCIENCE SUPPORTING CREATION (This site answers many arguments, both old and new, that have been used by evolutionists to support their theory)


    *I have given successful lectures (with question and answer period afterwards) defending creation before evolutionist science faculty and students at various colleges and universities. I’ve been privileged to be recognized in the 24th edition of Marquis “Who’s Who in The East” for my writings on religion and science.

    • Torbjörn Larsson | December 26, 2020 at 12:26 pm | Reply

      That is completely erroneous on science [c.f. “Evolution” @ Wikipedia for some examples showing it wrong, for example biology having no creationist ‘kinds’] as well as self promotion of links to irrelevant superstition.

  3. Torbjörn Larsson | December 26, 2020 at 12:22 pm | Reply

    Evolution is contingent and has irreversibility. The latter may also lock in simplification, i.e. the canonical genetic code gives you 20 amino acids and cells have to evolve add ons or modifications to use more.

    That said, this is interestingly simple locking in mechanism. Of course, it isn’t always irreversible or decisive:

    “Oligomeric proteins may have been selected for in hyperthermophiles because subunit association provides extra stabilization. Phosphoribosylanthranilate isomerase (PRAI) is monomeric and labile in most mesophilic microorganisms, but dimeric and stable in the hyperthermophile Thermotoga maritima (tPRAI).”
    [ https://www.sciencedirect.com/science/article/pii/S0969212600001064 ]

    Thornton is known for making ancestral protein reconstruction a useful area. “He is known for resurrecting ancestral genes and tracing the mechanisms by which proteins evolve new functions.” [“Joseph Thornton (biologist)” @ Wikipedia]

  4. Everything in our biology is continuously optimised by evolution. It may be that we have not discovered it use. That doesnt meant it has not use.

  5. …”A new study, at the University of Chicago, has shown, that elaborate protein structures accumulate over deep time, even when they serve no purpose, because a universal biochemical property and the genetic code force natural selection to preserve them.”…
    … And, that would be a proof, that nature “doesn’t know what it is doing”, and it is just random set of foolish mutations, that will generate emergence of new properties, that will carry on…
    … well, it is natural after all… Leave it to God’s …

  6. This article on complex proteins building up ever-increasing complexity for their own sake but without any purposeful function, reminds me of Freud’s writings on archaic power structures. These too, become increasingly complex over time, without doing any of us commoners any good. Look at the RCW codes, the minutiae in our tax laws, or the contraindication sheets accompanying every bottle of prescription pills. Another good analogy: The deforestation of our rain forests due to the stupendous writing and re-writing of the global warming problem. Here’s how the solution should read: Take a really big glass of warm water and drop a really big ice cube into the water. Icebergs float and can be transported to hot spots. Heat causes water to evaporate, evaporation makes clouds that make rain. Etc. Enough said

  7. All of what we know thru the lens of science didn’t happen by pure chance.To arrogantly conclude so would be absolutely foolish to do so.You would absolutely be confounded in the end of your journey in your quest for truth.There is quite a bit of evidence all around us if we really look without prejudice.Some intelligent Creator or force set things in motion with purpose.Some things we may think serves no purpose.However to the One who created that very thing we reject,has a purpose.The one who thinks it has no purpose is blind to the fact that it has.Also that very little insignificant protein bit may be the the vary thing that keeps the living living.In the tiny invisible world we don’t see is hidden for a reason.We only sense things within our spectrum of sight & sound,etc.If we are really brutally honest with ourselves,we will begin to sense that there is something much greater than we.This Intelligent Creator or force set everything in motion.So everything by design is self sustaining until that life form is challenged.Then those whatever proteins begin to do their thing & begin to help that life form to adapt to that environment.I’m just presenting this thought as a theory and not as sci.fact.

  8. This article appears to be a defence of the now disproven idea of ‘junk DNA’.


  9. The authors of this article seem to be unaware of the latest science/knowledge regarding the false idea of ‘Junk DNA’.


  10. … junk DNA, just a junk science…

  11. For a long while now, we’re aware of selfish genes. Essentially the blueprints of proteins. So it’s no surprise, given that there’s also imperfect duplication an recombination of DNA and RNA.

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