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One Amino Acid Can Be Enough

You know, we’re all mutants. No, not just those of us reading (or writing!) this web site, I mean all of us. We all have regions of our genome that are highly variable, of course – the sequences (often based on number of repeat markers) that are used in forensic DNA analysis or the mitochondrial regions used in paternity tests, for example – but we also have variations in all sorts of common DNA sequences as well. Single-nucleotide polymorphisms are everywhere, and if you sequence at enough depth you’ll find plenty of them. Most of these are silent, down in the difference-that-apparently-makes-no-difference category. But some of them aren’t.

Here’s an example of the latter: there’s a human developmental disorder called Floating-Harbor Syndrome (FHS) that leads to a number of phenotypic changes – facial abnormalities such as a small chin, large nose, deep-set eyes, along with general growth effects, language problems, high-pitched voice and others. It’s been traced back to a protein called SRCAP, which is involved in remodeling chromatin during gene expression. Various truncating mutations in that gene have been associated with FHS, and this new paper goes even further into the details.

An important function of SRCAP (and its partners in its chromatin remodeling complex) is to change histone interactions: the common H2A-H2B dimer is switched over to the H2A.Z-H2B dimer. That’s a rendering at right (via Wikipedia) of  DNA wound around H2A.Z, and gives you a picture of how this works. There’s an awful lot of that sort of thing going on during gene expression, and it’s safe to say that we don’t understand enough of the details, what with the genome being the size it is, and being wound and packaged at the level of complexity it is. There’s plenty of protein machinery dedicated to winding and unwinding particular regions to make them accessible (or inaccessible) for transcription, and this cannot be anything other than ferociously complex.  Consider the number of signals that can lead to differential gene expression under reasonable normal conditions in the cells of an adult organism (such as that oxygen-sensing system whose discovery just won the Nobel, for one), and then think of what must be going on during a complex organism’s development and embryogenesis. It’s pretty terrifying: at one end you have genes whose expression is flipping on and off constantly every hour of the day, and at the other you have particular combinations of genes that are critically important to be expressed just so at Day X and Day Y of embryo development and then must never be switched on in that way again after that time is done.

The H2A.Z variant of the “classic “H2A histone protein is already known to be important in a number of gene-expression programs. And just to add to the enjoyment, there are two varieties of H2A.Z, namely H2A.Z.1 and H2A.Z.2. These seem to have come about from a gene-duplication event way back when in evolutionary time and (as is customary) there has been some drift between the two since then and our cells seem to have found a way to make use of the two variants. They differ only in three amino acids, and while most of the older literature considers them to be the same thing (all just H2A.Z), it’s becoming clearer that they can have different roles.

And this paper certainly nails that down! In both Xenopus (frog) and human cells, the authors (from Stanford) show that the H2A.Z.1 and 2 subtypes are quite different when it comes to FHS. The effects of SRCAP truncations, for example, appear to come from a deficiency of SRCAP (rather than it exerting a negative effect), and these can be at least partially rescued by supplying more H2A.Z.2. Even further, it appears that this rescue is mediated by just one of the three different amino acid residues: mutating a serine at position 38 to a threonine is enough by itself to show the effect. And that is a pretty conservative change! Threonine has an extra methyl group in the side chain, on the carbon next to the hydroxy, and that’s it. But that’s enough.

Which takes me back to what I started with in the first paragraph: the nonlinearity of biology. There are so many places that you could make a single-residue change like this in the human proteome and nothing noticeable would happen – but not here. The analogy I used several years ago (while talking about mutations that lead to early-onset Alzheimer’s) was that if you could reduce molecular biology to a huge equation, it would have thousands and thousands of terms in it, with many of the coefficients in front of them being (most of the time) close to zero and thus not important. But some of those, if they ever do get an actual coefficient that lets them pop up out of the noise, have huge exponents hiding in them that can make them suddenly, wildly important. It need hardly be added that this situation is an absolute nightmare for anyone who might actually be trying to produce such a mathematical/computational model (!) But that’s the reality. . .

17 comments on “One Amino Acid Can Be Enough”

  1. loupgarous says:

    “There are so many places that you could make a single-residue change like this in the human proteome and nothing noticeable would happen – but not here. The analogy I used several years ago (while talking about mutations that lead to early-onset Alzheimer’s) was that if you could reduce molecular biology to a huge equation, it would have thousands and thousands of terms in it, with many of the coefficients in front of them being (most of the time) close to zero and thus not important. But some of those, if they ever do get an actual coefficient that lets them pop up out of the noise, have huge exponents hiding in them that can make them suddenly, wildly important. It need hardly be added that this situation is an absolute nightmare for anyone who might actually be trying to produce such a mathematical/computational model “

    To a software specialist, that relationship isn’t so strange. Those changes in gene expression are “bits” whose significance changes with the program timing enormously – they “call macros” that at the right time determine what your program will do much more than the relatively simple code that calls them.

  2. Derek Jones says:

    Talking of DNA forensics, I hear a potential start-up is looking for a chairman of the board. Any suggestions 😉
    http://shape-of-code.coding-guidelines.com/2019/09/15/team-dna-impersonators-create-a-business-plan/

    1. loupgarous says:

      It seems to me that organized crime (the only kind with the profit margins capable of making “custom” or “bespoke” DNA sequencing of criminals pay) consists of the people who have the money at the top of the criminal food chain, giving orders to the much less valuable thieves, contract murderers, smugglers, meth cooks and so forth, whose lives and/or freedom are much more expendable.

      Of course, I could be wrong, and some individual hoodlums might be so productive and have such unique skill sets that it would pay them (or their patrons) to keep them unindictable by widely disseminating their DNA in the populace at large (say, a very infectious AAV .

      One scary way of doing that would be a non-pathogenic but very communicable AAV that could be used to CRISPR a potential criminal suspect’s identifiable genetic sequences into the general public’s DNA, so that the odds against having those particular DNA sequences drop precipitously. The Jeff Bezos of future organized crime might attack the problem from both sides, using CRISPR to make his minions less geneticaly conspicuous and making that inconspicuous set of sequences ubiquitous in the general populace.

      English physicist Charles Sheffield’s SF short story “Dancing with Myself” describes something similar, a viral “DNA converter” developed for cancer research which accidentally “gets loose”, eventually converting much of the human race’s genome to the pattern of the kindly woman scientist who helped create the “converter” – quietly creating a planet of people less inclined to aggression (on the questionable theory that behavior has such a biological component that this could happen). It was plausible enough to make a good read when I first read the story in Analog in 1989, but only took a little reflection to fall apart – “humoral” causes for misbehavior aren’t the sole source of mischief in the world..

      1. Derek Jones says:

        The cost of marketing may make it uneconomic to sell to all comers; readers of this blog will know more about drug marketing than me. The Police present at the hackathon were uncertain what the legality of selling such a product (there were no high powered lawyers present, or at least they did not volunteer this information).

        One large potential market are people at demonstrations, e.g., the Hong Kong protests. I can certainly see the Chinese government cracking down on this usage.

    2. Patrik says:

      I wonder whether this will be a sustainable business model. We are already able to identify people who died tens of thousands of years ago from tiny amounts of highly fragmented DNA by using a chip analysing 1.2 mio SNPs spread across the genome – so it shouldn’t be too difficult to change the identification method. But perhaps someone manages to purchase a few shake flasks and a cow for bovine serum and produces a few liters of HeLa cells – the famous cancer cell line derived from a tumor of Henrietta Lacks. (You don’t even need to isolate the DNA). Spreading these cells at the crime scene would cause some headache also for the chip guys. Business plan is in the works.

  3. Peter S. Shenkin says:

    “the mitochondrial regions used in paternity tests”

    Since the mitochondrial DNA is inherited only from the mother, I don’t think it can be used for paternity testing. Maybe you meant maternity testing?

    1. Klagenfurt says:

      Hmm, not suitable for maternity testing either. Your biological mother could blame it on her sister or, after consultation with me, on her maternal female 1st, 2nd, 3rd etc. cousin.

      1. Peter S. Shenkin says:

        Makes sense, but on the other hand, a failure to match is definitive.

  4. Steve says:

    small chin, large nose, deep-set eyes, high-pitched voice – have I had FHS syndrome all this time without knowing?

    1. Isidore says:

      I don’t suppose there is necessarily a one-to-one relationship between the genotype and the FHS syndrome phenotype.

  5. Methyl says:

    Just like modifications. Only now are we starting to see how they impact proteins globally

  6. zero says:

    I kept reading that protein acronym as SCRAP, over and over. Thanks brain, but autocorrect isn’t helping right now.

    Hopefully we make some headway on that issue of DNA packing. It would be nice to bring some order to that chaos, even if the description will probably be beyond most of us.

    1. Derek Lowe says:

      I kept typing it that way, too. You’re not alone.

  7. Greg says:

    Derek – I feel like this is another situation where you are unfairly in my view singling out biological modeling. These sorts of non-linearities also impede qualitative, researcher-driven reasoning around biology too!

    1. Derek Lowe says:

      Oh, no doubt. And my mention of modeling was more of a thought experiment – is there anyone really trying to put together an explicit mathematical model of that sort?

    2. Mol biologist says:

      There are few legends that some NOVEL writers used other writers as slaves because they are getting tired from writing itself.https://en.wikipedia.org/wiki/William_Shakespeare%27s_collaborations
      IMO biology rule sounds very impressive regarding metabolic switcher if you need to slow down and accumulate some nutrients at stress or development situations.
      For example, during the development of drosophila JH suppresses ecdysone biosynthesis and inhibits metamorphosis, whereas 20E suppresses JH biosynthesis and promotes metamorphosis.
      https://www.pnas.org/content/115/1/139
      In plants, the repressive role of H2A.Z in transcription sounds very logical because flowering and seeding need a lot of resources. However, authors found that H2A.Z MonoubiquitinatioN plays an important role in the transcriptional repression mediated by this histone variant, emerging as a key factor to understand H2A.Z function in gene regulation.
      https://www.nature.com/articles/s41467-019-10773-1

  8. Barry says:

    That a single AA change can be the difference between wt and disease is long-established. See “sickle cell”. In that case, the mutation affects one protein and one function of that haemoglobin. Here, that single AA change affects a whole suite of protein expression (and tool correspondingly longer to elucidate.)

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