Origin of complexity in haemoglobin evolution -- newest from Thornton lab

Important new paper from Joe Thornton and colleagues, on the evolution of molecular complexity. Here is the accompanying News and Views piece:

https://www.nature.com/articles/d41586-020-01287-8

Key quote from the News and Views article:

The authors’ work shows how natural selection, acting on pre-existing biophysical protein properties, can, in just a few evolutionary steps, create multimeric structures that have complex functions. Most cellular processes involve the action of protein multimers, and Pillai and colleagues’ work serves as one of the clearest examples so far of how such complexity can arise during protein evolution.

The piece also explores caveats and future directions.

Link below to the primary article itself, and abstract is below. I can help you get a PDF if you get in touch.

https://www.nature.com/articles/s41586-020-2292-y

Abstract
Most proteins associate into multimeric complexes with specific architectures1,2, which often have functional properties such as cooperative ligand binding or allosteric regulation3. No detailed knowledge is available about how any multimer and its functions arose during evolution. Here we use ancestral protein reconstruction and biophysical assays to elucidate the origins of vertebrate haemoglobin, a heterotetramer of paralogous α- and β-subunits that mediates respiratory oxygen transport and exchange by cooperatively binding oxygen with moderate affinity. We show that modern haemoglobin evolved from an ancient monomer and characterize the historical ‘missing link’ through which the modern tetramer evolved—a noncooperative homodimer with high oxygen affinity that existed before the gene duplication that generated distinct α- and β-subunits. Reintroducing just two post-duplication historical substitutions into the ancestral protein is sufficient to cause strong tetramerization by creating favourable contacts with more ancient residues on the opposing subunit. These surface substitutions markedly reduce oxygen affinity and even confer cooperativity, because an ancient linkage between the oxygen binding site and the multimerization interface was already an intrinsic feature of the protein’s structure. Our findings establish that evolution can produce new complex molecular structures and functions via simple genetic mechanisms that recruit existing biophysical features into higher-level architectures.

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Just saw this on twitter, and was about to post it!

It’s always a good day when the Thornton lab published a new paper!

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Yep. One of a handful of people who’s work I’ve been following intensely ever since I first became aware of it. I continue to be amazed that it is possible for scientists to say with considerable confidence that a particular mutation occurred in some particular gene billions of years ago, and what it’s physical and chemical, and hence phenotypic effects would have been.

Ancestral sequence reconstruction methods and the results that can be derived therefrom really deserve to be much more widely known. It is nothing short of amazing.

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There are only three different DNA strands used for haemoglobin production in human genome. These genes are HBA1, HBA2 and HBB

http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000206172;r=16:176680-177522
https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000188536;r=16:172876-173710
https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000244734;r=11:5225464-5229395

Hemoglobin subtypes and other differences in haemoglobins are results of alternative splicing and other epigenetic regulation.

HBA1 - 4 splice variants
HBA2 - 4 splice variants
HBB - 6 splice variants

So, every human haemoglobin types are based on one of these three sequences and epigenetic regulation of transcription from them.

Alternative splicing is not considered “epigenetic regulation.”

Whether or not this is true, it’s not relevant to the thread.

There are several more alpha and beta globin genes, as these exist in clusters (along with multiple pseudogenes). However, this may be beside the point you are trying to make here. What is that point?

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//Whether or not this is true, it’s not relevant to the thread.//

Of course it’s relevant. Why do you talk about evolution? Human hemoglobin diversity is based on epigenetic regulation. Epigenetic modifications never result in any kind of evolution but devolution.

The evidence suggests that the hemoglobin diversity is based on simple (and very common) duplication and divergence.

https://www.sciencedirect.com/topics/neuroscience/globin-gene

All of that is false. Good day!

HBB gene: 27 disease phenotypes. Evidence for genetic decay.
HBA1 gene: 9 disease phenotypes. Evidence for genetic decay.
HBA2 gene: 7 disease phenotypes. Evidence for genetic decay.

Still only three different DNA strands used for hemoglobin protein encoding in human genome worldwide. There’s more genetic entropy than true beneficial genetic variants. Where’s the evolution?

its seems that the globin complexity is basically the same in both primitive and modern creatures (at least for myoglobin):

so where is the evolution actually?

(image from PDB-101: Molecule of the Month: Globin Evolution)

What do you see in this figure that suggests that globin complexity (it might be helpful to define what you mean here, as well) is “basically the same in both primitive and modern creatures”? Each of these drawings is from a modern creature.

indeed. but this is after the fact explanation. we can check it at the genomic level too. we know for instance that some of the most ancient creatures (sponges for instance) had a genome that is no less complex from that of a modern creature (human for instance). so the most primitive creatures are no less complex than modern creatures.

So as we can see, the ancestor used to consist of just a single protein subunit, a monomer. This got duplicated, creating a homodimer (homo because there’s two of the same subunits connected to each other, dimer because there’s two).

The two duplicates diverged (mutations made them different from each other), resulting in a hetero(different) dimer.
Eventually they evolved to be able to assemble into a tetramer with four subunits, consisting of two heterodimers.

The proteins share an ancient common ancestor with myglobin.

That’s an example of evolution of increased molecular complexity. From a complex consisting of a single protein subunit, to one consisting of four. From a single ancestral protein coding gene, into multiple distinct protein coding genes with different functions, including the distinct functional protein coding genes of both hemoglobin and myoglobin.

Did you read the actual research article linked in the OP? It describes the evolution of the hemoglobin tetramer(consisting of four subunits, as in tetra), as in the quaternary structure of the extant hemoglobin protein complex, from an ancient precursor with only one subunit. It happened by multiple successive rounds of duplication and divergence.

Key ancestral stages in this evolutionary history are inferred by phylogenetic methods, recreated in the laboratory, and tested for how they worked and which mutations made it possible for the transition from a single subunit to four interconnected subunits to evolve.

That’s where the evolution is.

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Sorry, but the only sponge genomes you know about are modern sponges, which are not ancient at all. In order to make any inference about ancient sponges, you would have to make use of phylogenetic inference. But you reject that, so you can’t really say anything about the subject. Your claim also suffers from the equating of genomic complexity with phenotypic complexity; it seems you are unacquainted withe the c-value paradox.

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Sponge genome sizes vary 17-fold, so yeah…

https://doi.org/10.1139/gen-2012-0122

Gene duplication per se doesn’t lead to homodimerisation.

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You’re right, that was stated incorrectly. The Ancα/β ancestor is actually a pre-duplication protein that intrinsically forms homodimers. It was only after this got duplicated and the two duplicates diverged it became a heterodimer.

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